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1
Järås, Marcus, Peter G. Miller, Lisa Chu, Rebekka K. Schneider, Rishi V. Puram, Fatima Al-Shahrour, Emma Fink, et al. "Casein Kinase 1 Alpha Maintains Normal and Leukemic Stem Cells by Regulating p53 Activity." Blood 120, no. 21 (November 16, 2012): 209. http://dx.doi.org/10.1182/blood.v120.21.209.209.
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Abstract Abstract 209 In order to identify novel approaches to the targeting of acute myeloid leukemia (AML), we performed a pooled in vivo shRNA screen on murine leukemic stem cells (LSCs) targeting factors related to Wnt-signaling. We found that silencing of casein kinase 1 alpha (Csnk1a1), a serine-threonine kinase and a critical negative regulator of beta catenin, dramatically depleted murine LSCs in vivo. This is a surprising result since beta catenin is essential for MLL-AF9 AML. Validation experiments with shRNA vectors co-expressing GFP recapitulated the result from the pooled screen and confirmed efficient knockdown of both the Csnk1a1 transcript and protein. To rule out off-target effects of the Csnk1a1 shRNAs, we co-expressed the shRNAs with a Csnk1a1 cDNA mutated at the shRNA binding sites, and observed a complete rescue of the proliferative defect. Additionally, we demonstrated that a kinase dead form of Csnk1a1(D136N) failed to rescue this proliferation defect. These results indicate the specific effect of these hairpins on Csnk1a1 function in leukemia cells. The role of Csnk1a1 in normal hematopoietic stem and progenitor cells (HSPCs) is not known. We introduced the Csnk1a1 shRNA vectors into HSPCs and followed GFP over time in a bone marrow transplantation setting. Over a 24-week period, we observed a 3–4 fold depletion of GFP positive donor cells with two independent Csnk1a1 shRNAs compared to control. In contrast, the same shRNAs resulted in a 20–25 fold depletion of leukemia cells in vivo over a 2-week time period, suggesting that leukemia cells are selectively dependent on Csnk1a1. To more rigorously study Csnk1a1 in hematopoiesis, we generated a Csnk1a1 conditional knockout mouse (loxP sites flanking critical exon 3) and crossed it with the Mx1-cre mouse, allowing for hematopoietic specific inducible Csnk1a1 excision. In competitive bone marrow transplantations, Csnk1a1(−/−) donor cells exhibited a severe competitive disadvantage resulting in a 20-fold depletion of donor cells over a 12-week period. Interestingly, Csnk1a1(−/−) donor cells were devoid of myeloid lineage cells, suggesting that Csnk1a1 is particularly important for the generation or survival of myeloid cells. Moreover, in line with our shRNA results, we found that Csnk1a1(−/−) cells were resistant to MLL-AF9 mediated transformation, demonstrating that Csnk1a1 is essential also for leukemia initiation. To identify critical targets of Csnk1a1, we performed gene expression profiling of Csnk1a1 silenced cells. We identified enrichment of a p53 signature using Gene Set Enrichment Analysis (FDR= 0.001). Induction of p53 and its target p21 was confirmed by western blots in both Csnk1a1 silenced leukemia cells and in Csnk1a1(−/−) bone marrow cells. Furthermore, we demonstrated that p53(−/−) leukemia cells are resistant to the proliferative defect induced by Csnk1a1 silencing. We next tested whether D4476, a small molecule casein kinase inhibitor, would exhibit selective anti-leukemic effects. Whereas treatment of LSCs with D4476 inhibited their proliferation (IC50: 7μM), concentrations up to 40μM had minimal effects on normal HSPCs. Confirming the specificity of the compound, we found that cells carrying Csnk1a1 shRNAs were sensitized to D4476 in a dose dependent manner. In contrast, overexpression of Csnk1a1 desensitized leukemia cells for D4476 treatment, suggesting that D4476 kills leukemia cells in a Csnk1a1 dependent manner. Finally, we mixed 10,000 HSPCs with 10,000 LSCs and treated them ex vivo with either D4476 or DMSO control for 48 hours followed by injection into lethally irradiated mice. Whereas exposure to the drug caused prolonged latency of disease with some recipients never developing leukemia, there was no significant effect on HSPC donor cell chimerism at 8 weeks post transplantation compared control, indicating limited toxicity from the drug. In summary, these findings identify Csnk1a1 as critical for maintaining both normal HSCs and LSCs via modulation of p53 activity. Importantly, LSCs were significantly more sensitive to small molecule inhibition of Csnk1a1, suggesting that Csnk1a1 may be an attractive new drug target in AML. Disclosures: No relevant conflicts of interest to declare.
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Fink, Emma C., Jan Krönke, Slater N. Hurst, Namrata D. Udeshi, Tanya Svinkina, Rebekka K. Schneider, Marie E. McConkey, et al. "Lenalidomide Induces Ubiquitination and Degradation of CSNK1A1 in MDS with Del(5q)." Blood 124, no. 21 (December 6, 2014): 4. http://dx.doi.org/10.1182/blood.v124.21.4.4.
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Abstract The immunomodulatory (IMiD) drug lenalidomide is a highly effective treatment for multiple myeloma and myelodysplastic syndrome (MDS) with deletion of chromosome 5q (del(5q)). Recently, we and others demonstrated that lenalidomide activates the CRBN-CRL4 E3 ubiquitin ligase to ubiquitinate IKZF1 and IKZF3. Degradation of these lymphoid transcription factors explains lenalidomide’s growth inhibition of multiple myeloma cells and increased IL-2 release from T cells. However, it is unlikely that degradation of IKZF1 and IKZF3 accounts for lenalidomide’s activity in MDS with del(5q). Instead, we hypothesized that ubiquitination of a distinct CRBN substrate in myeloid cells explains the efficacy of lenalidomide in del(5q) MDS. Applying quantitative proteomics in the myeloid cell line KG-1, we identified a novel target, casein kinase 1A1 (CSNK1A1), that had increased ubiquitination and decreased protein abundance following lenalidomide treatment. CSNK1A1 is encoded in the del(5q) commonly deleted region and is thus a potential lenalidomide target in del(5q) MDS. Previous studies have demonstrated that Csnk1a1 is a therapeutic target in a murine model of acute myeloid leukemia. We validated that lenalidomide treatment decreased CSNK1A1 protein levels in multiple human cell lines in a dose-dependent manner without altering CSNK1A1 mRNA levels. Moreover, lenalidomide treatment increased ubiquitination of CSNK1A1 in cell lines. The decrease in CSNK1A1 protein levels in response to lenalidomide was abrogated by treatment with the proteasome inhibitor MG132 and by Cullin-RING ubiquitin ligase inhibition with MLN4924. CSNK1A1 co-immunoprecipitated with CRBN in the presence of lenalidomide, demonstrating direct interaction of CSNK1A1 with the substrate adaptor for the ubiquitin ligase. Homozygous genetic inactivation of the CRBN gene by CRISPR/Cas9 genome editing in 293T cells eliminated lenalidomide-induced degradation of CSNK1A1. In aggregate, these experiments demonstrate that CSNK1A1 is a CRBN-CRL4 substrate that is ubiquitinated and degraded in the presence of lenalidomide. We next explored how degradation of CSNK1A1 might explain the specificity of lenalidomide for cells with del(5q). ShRNA-mediated knockdown of CSNK1A1 sensitized primary human CD34+ cells to lenalidomide treatment, indicating that haploinsufficiency for CSNK1A1 might increase lenalidomide sensitivity in del(5q) hematopoietic cells. We sought to further validate this finding in a genetically defined Csnk1a1 conditional knockout mouse model. While murine cells are resistant to the effects of IMiDs, murine Ba/F3 cells overexpressing human CRBN (hCRBN), but not murine CRBN, degraded CSNK1A1 in response to lenalidomide. To examine the effect of Csnk1a1 haploinsufficiency on lenalidomide sensitivity, we isolated hematopoietic stem and progenitor cells from Csnk1a1+/- and Csnk1a1+/+ mice and transduced them with a retroviral vector expressing hCRBN. When treated with lenalidmide, Csnk1a1+/- cells expressing hCRBN were depleted over time relative to wild-type controls. The enhanced sensitivity of Csnk1a1+/- cells to lenalidomide was associated with induction of p21 and was rescued by heterozygous deletion of p53, demonstrating a critical downstream role for p53 consistent with clinical observations that TP53 mutations confer lenalidomide resistance. In aggregate, these studies demonstrate that lenalidomide induces the ubiquitination and consequent degradation of CSNK1A1 by the CRBN-CRL4 E3 ubiquitin ligase. del(5q) cells have only one copy of CSNK1A1, so they are selectively depleted over wild-type cells, explaining lenalidomide’s clinical efficacy in del(5q) MDS. Although the idea that heterozygous deletions could be cancer vulnerabilities was first proposed 20 years ago, lenalidomide provides the first example of an FDA-approved and clinically effective drug that derives its therapeutic window from specifically targeting a haploinsufficient gene. Disclosures Ebert: Celgene: Research Funding; Genoptix: Consultancy.
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Stalmann, Ursula S. A., Fabio Ticconi, Ronghui Li, Aaron B. Wong, Glenn Cowley, David E. Root, Dirk Heckl, et al. "Deconstructing the Clonal Advantage and Clonal Stability of 5q- Candidate Genes in Del(5q) MDS on a Single Cell Level." Blood 134, Supplement_1 (November 13, 2019): 559. http://dx.doi.org/10.1182/blood-2019-122588.
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Hematopoietic Stem/Progenitor cells (HSPCs) with 5q haploinsufficiency in del(5q) myelodysplastic syndrome (MDS) acquire a clonal advantage in the bone marrow and out-compete normal hematopoiesis. A critical, yet unsolved question remains: how does genetic haploinsufficiency in del(5q) cells contribute to the clonal advantage of HSPCs? We investigated the role of haploinsufficiency for three candidate genes in the common deleted region on chromosome 5 (Csnk1a1, Egr1 and Apc) in direct competition with each other and wild-type (wt) cells on a single cell level by employing a novel lentiviral genetic barcoding strategy. We introduced genotype and cell-specific barcodes into HSPCs from murine models haploinsufficient for Csnk1a1, Egr1 or Apc. Barcoded HSPCs were sort-purified, genotypes mixed and subsequently competitively transplanted into lethally irradiated mice and re-transplanted after 16 weeks in a secondary transplant. The barcoded progeny was reliably recovered from peripheral blood and relative contribution of the barcoded clones to differentiated blood lineages was followed over 32 weeks. Despite heterogeneity in clonal evolution among the mice, all haploinsufficient clones had the potential to outcompete wt clones (3 of 5 mice in the primary transplant, 3 out of 4 mice in the secondary transplant). Csnk1a1 haploinsufficient clones showed the largest clonal abundance and clonal persistence. Expansion of oligoclonal Csnk1a1 haploinsufficient HSPCs was further enhanced in the secondary transplant in all mice. Egr1 haploinsufficient clones showed potential for prominent oligoclonal expansion in one mouse, but decreased in abundance in all secondary transplants. Apc haploinsufficient clones showed persistence but not expansion in 3 out of 5 mice. These results were validated by conventional competitive transplants, which demonstrated that Csnk1a1 and Egr1 haploinsufficient cells achieved the highest advantage over wt hematopoiesis in the primary transplant and more enhanced in the secondary transplant. Since Csnk1a1 regulates β-catenin protein stability, we hypothesized that the clonal expansion of Csnk1a1 haploinsufficient HSPCs is dependent on β-catenin levels. We performed a second genetic barcoding competitive transplant, comparing Csnk1a1-/+ HSPC directly to double haploinsufficient Csnk1a1-/+/Ctnnb1-/+ (β-catenin encoding) HSPCs. We included additional double haploinsufficient mutants Csnk1a1-/+/Apc-/+ and Csnk1a1-/+/Egr1-/+. Results showed pronounced expansion of Csnk1a1-/+ clones, while Csnk1a1-/+/Ctnnb1-/+ clones were outcompeted over time, suggesting that the advantage of Csnk1a1-/+ clones is β-catenin dependent. Csnk1a1-/+/Egr1-/+ and Csnk1a1-/+/Apc-/+ clones were less advantageous than Csnk1a1-/+ clones. To further investigate the mechanism of clonal fitness in Csnk1a1-/+ haploinsufficient HSPCs, we performed droplet based single cell RNA sequencing of Csnk1a1-/+ and wt Lin-Sca1+cKit+ (LSK) HSPCs. Csnk1a1 -/+ LSK were characterized by a higher fraction of cells expressing cell cycle genes compared to wt cells. In line, transcriptional alterations in the most primitive HSCs suggest that the clonal advantage is conveyed by canonical Wnt signaling activating downstream targets such E2F proteins. Csnk1a1-/+ haploinsufficient multipotent progenitors and myeloid/lymphoid primed progenitors expressed marked upregulation of metabolic pathways, mitochondrial respiration, cell cycle and differentiation, ubiquitination/proteasome system and deregulation of ribosome biogenesis. In conclusion, we demonstrate using a novel genetic barcoding approach in a competitive transplant setting that Csnk1a1-/+ haploinsufficient HSPCs have the potential for oligoclonal expansion and clonal persistence. Wnt/β-catenin signaling plays a central role in the clonal expansion. Interestingly, in Csnk1a1 haploinsufficiency the HSC state is preserved and the increased proliferation and metabolic activation are hallmark features of differentiating progenitor cells at MPP stage, increasing with cell cycle activation, thus ensuring clonal stability and preventing HSC exhaustion over time. Disclosures Brümmendorf: University Hospital of the RWTH Aachen: Employment; Janssen: Consultancy; Pfizer: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy, Research Funding; Ariad: Consultancy. Ebert:Celgene: Research Funding; Deerfield: Research Funding; Broad Institute: Other: Contributor to a patent filing on this technology that is held by the Broad Institute..
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Järås, Marcus, Peter G. Miller, Lisa P. Chu, Rishi V. Puram, Emma C. Fink, Rebekka K. Schneider, Fatima Al-Shahrour, et al. "Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia." Journal of Experimental Medicine 211, no. 4 (March 10, 2014): 605–12. http://dx.doi.org/10.1084/jem.20131033.
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Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML.
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Heuser, Michael, Manja Meggendorfer, Michelle Maria Araujo Cruz, Larissa Koehler, Gudrun Goehring, Christina Ganster, Annika Gutermuth, et al. "Casein Kinase 1A1 (CSNK1A1) Is Recurrently Mutated in MDS Patients with Deletion of Chromosome 5q." Blood 124, no. 21 (December 6, 2014): 4643. http://dx.doi.org/10.1182/blood.v124.21.4643.4643.
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Abstract Background and Aim: Deletion of 5q is the most frequent cytogenetic aberration in MDS and is associated with distinct clinical characteristics, disease course and sensitivity to lenalidomide. The serine-threonine kinase CSNK1A1 is located in the commonly deleted region at 5q32 and has been described as a tumor-suppressor gene in colon cancer and acute myeloid leukemia through regulation of ß-catenin and p53. Recently, missense mutations in CSNK1A1 have been described in individual patients with del(5q) MDS. The aim of our study was to characterize the frequency and potential prognostic impact of CSNK1A1mutations in MDS and AML following MDS. Methods: 192 patients with MDS or AML following MDS (sAML) and deletion of chromosome 5q and 406 patients with MDS/sAML without deletion of chromosome 5q were included in the current analysis (n=598 in total). Patients with MDS (n=442) or sAML (n=156) were cytogenetically characterized by chromosome banding analysis and molecularly analyzed for mutations in exon 3 and 4 of CSNK1A1, the region critical for the kinase function, by Sanger sequencing. Patients with mutated CSNK1A1 were also analyzed for mutations in TP53 by next-generation or Sanger sequencing. Results: CSNK1A1 mutations were found in 17 (8.9%) of 192 MDS patients with del(5q). The mutation frequency was similar between patients with isolated del(5q) (n=153) and patients with concurrent cytogenetic aberrations or missing additional cytogenetic information (n=39)(9.2% vs 7.7%, P=.7). No mutation of CSNK1A1 was found in any of 406 MDS/sAML patients without del(5q). Thirteen patients (76%) had missense mutations affecting amino acid E98 in exon 3 of CSNK1A1. Of these, the glutamic acid to lysin substitution was the most frequent amino acid substitution (n=7). All mutations of glutamic acid 98 had a high probability to be damaging to the protein based on PolyPhen2 predictions (scores 0.922 to1). One patient had an Asn86Tyr mutation concurrently with the Glu98Ala mutation. Four patients (24%) had missense mutations affecting aspartic acid 140 in exon 4 of CSNK1A1. These mutations had moderate PolyPhen2 prediction scores (0.558-0.798). Three of the 17 CSNK1A1 mutated patients had additional cytogenetic aberrations besides del(5q), i.e. one trisomy 8, one trisomy 11, and one monosomy 7. None of the CSNK1A1 patients had a concurrent TP53 mutation. Del(5q) patients with wildtype or mutated CSNK1A1 had a similar median age (73.3 vs 77.5 years, P=.15). 70% and 59% of wildtype and mutated CSNK1A1 patients had female sex, respectively (P=.33). The WBC count was similar between wildtype and mutated CSNK1A1patients (3.9 vs 4.6, P=.47). Survival information was available for 155 patients with del(5q) (81%) including 16 patients (94%) with mutated CSNK1A1. Median follow-up from the time of sample harvest was 2.02 years. The probability of survival at 2 years was 41% for CSNK1A1 mutated and 72% for CSNK1A1wildtype patients (P=.059, log-rank test), suggesting a potential negative prognostic impact of CSNK1A1 mutations in del(5q) MDS patients. Conclusion: CSNK1A1 mutations are highly specific for MDS patients with del(5q) and are one of the most frequent recurrent genetic aberrations in these patients. Our survival analysis suggests that CSNK1A1 mutations have an unfavorable prognostic effect in patients with MDS and del(5q); however, the prognostic impact has to be confirmed in additional patients. Mutation analysis of exon 3 and 4 of CSNK1A1 should be included in the routine workup of MDS patients with deletion of 5q. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Kobbe:Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Medac: Other; Astellas: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Other. Haferlach:MLL: Equity Ownership.
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Stegmaier, Kimberly. "Targeting Csnk1a1 in leukemia." Journal of Experimental Medicine 211, no. 4 (April 7, 2014): 594. http://dx.doi.org/10.1084/jem.2114insight1.
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Rebekka, Schneider K., Monica Schenone, Monica Ferreira Ventura, Fabian Beier, Tim H. Bruemmendorf, Ulrich Germing, Uwe Platzbecker, et al. "Cooperating Effect of Rps14, Csnk1a1 and miRNA145/miRNA146a Haploinsufficiency in the Activation of the Innate Immune System in Del(5q) MDS." Blood 126, no. 23 (December 3, 2015): 356. http://dx.doi.org/10.1182/blood.v126.23.356.356.
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Abstract Heterozygous deletion of RPS14 occurs in del(5q) MDS and has been linked to impaired erythropoiesis, characteristic of this disease subtype. We previously generated a mouse model with conditional inactivation of Rps14 and demonstrated a p53-dependent erythroid differentiation defect with apoptosis at the transition from polychromatic to orthochromatic erythroblasts resulting in age-dependent progressive anemia, megakaryocyte dysplasia, and loss of hematopoietic stem cell (HSC) quiescence. We now sought to determine the mechanistic basis for the anemia using unbiased, quantitative mass spectrometry in erythroid progenitor cells. We found powerful induction of proteins involved in innate immune signaling, particularly the danger associated molecular pattern (DAMP) heterodimeric S100A8/S100A9 proteins. We found significantly increased S100a8 in the erythroid progenitor populations affected by the differentiation block (RIII-RIV population) and in monocytes and macrophages of Rps14 haploinsufficient bone marrows, all representing cells of the erythroblastic niche. Recombinant S100A8 was sufficient to impair erythropoiesis in wild-type cells. We rescued the erythroid differentiation defect in Rps14 haploinsufficient HSCs by genetic inactivation of S100a8 expression using CRISPR/Cas-mediated gene inactivation in primary mouse Rps14 haploinsufficient HSPC. We validated the association between induction of S100A8 and a severe erythroid phenotype in bone marrow samples of patients with del(5q) MDS. To examine whether ribosomal haploinsufficiency also leads to activation of S100A8 in patients with del(5q) MDS, we measured S100A8 expression using immunofluorescence in bone marrow biopsies from MDS patients with and without del(5q). In del(5q) MDS, the frequency of S100A8-positive cells was associated with disease severity, as reflected by transfusion burden. RPS14, CSNK1A1 and miR-145 are universally co-deleted in the 5q- syndrome and each represent different clinical features of del(5q) MDS in murine models. Haploinsufficiency of miR-145 or -146a also induces inappropriate activation of innate immune signaling. To analyze the combinatorial effect of haploinsufficiency Rps14, Csnk1a1 and miRNA-145, we transduced hematopoietic stem and progenitor cells (HSPC) from compound haploinsufficient Rps14 and Csnk1a1 mice and stably knocked down both miR-145/miR-146a by retrovirus-mediated overexpression of respective target sequences. Compound haploinsufficiency of Rps14, Csnk1a1 and miR-145/146a led to a progressive anemia comparable to Rps14 haploinsufficiency with splenomegaly and an erythroid differentiation defect at the RIII/RIV population, indicating that the anemia is mainly driven by Rps14 haploinsufficiency. Bone marrow histology demonstrated the typical 5q-phenoytpe of megakaryocytes, in line with significant thrombocytosis. At 10 months of age, hematopoietic stem and progenitor cells were significantly increased (lineagelow ckit+ Sca1+; LSK), in particular multipotent progenitor cells (MPPs; lineagelow ckit+ Sca1+ CD48- CD150+) to significantly higher extents than in solely Rps14 or Csnk1a1 haploinsufficient cells. We next asked if compound haploinsufficiency of the three 5q-genes has combinatorial or synergistic effects on S100a8 expression. Compound haploinsufficiency of Csnk1a1, Rps14 and miR-145/146a induced the highest expression of S100a8 in monocytes, while haploinsufficiency of Rps14 alone induced the highest expression of S100a8 in the RIII erythroid population, suggesting that cell-type specific induction mediates the phenotype. Our data indicate an unexpected link between haploinsufficiency for a ribosomal gene, Rps14, activation of S100A8, and inhibition of erythropoiesis. We demonstrate that compound haploinsufficiency for Csnk1a1 and miR145/146a with Rps14 haploinsuffciency increases the expression of S100a8, mainly in monocytes, and recapitulates the phenotype of del(5q) MDS by cooperating, cell-type specific effects. Disclosures Platzbecker: Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Boehringer: Research Funding.
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Boultwood, Jacqueline, and Andrea Pellagatti. "Clinical associations of CSNK1A1 mutation in myelodysplastic syndrome." Lancet Haematology 2, no. 5 (May 2015): e182-e183. http://dx.doi.org/10.1016/s2352-3026(15)00070-8.
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Mishra, Seema. "CSNK1A1 and Gli2 as Novel Targets Identified through an Integrative Analysis of Gene Expression Data, Protein–Protein Interaction and Pathways Networks in Glioblastoma Tumors: Can these Two be Antagonistic Proteins?" Cancer Informatics 13 (January 2014): CIN.S18377. http://dx.doi.org/10.4137/cin.s18377.
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Glioblastoma (GBM) is the malignant form of glioma, and the interplay of different pathways working in concert in GBM development and progression needs to be fully understood. Wnt signaling and sonic hedgehog (SHH) signaling pathways, having basic similarities, are among the major pathways aberrantly activated in GBM, and hence, need to be targeted. It becomes imperative, therefore, to explore the functioning of these pathways in context of each other in GBM. An integrative approach may help provide new biological insights, as well as solve the problem of identifying common drug targets for simultaneous targeting of these pathways. The beauty of this approach is that it can recapitulate several known facts, as well as decipher new emerging patterns, identifying those targets that could be missed when relying on one type of data at a time. This approach can be easily extended to other systems to discover key patterns in the functioning of signaling molecules. Studies were designed to assess the relationship between significant differential expression of genes of the Wnt (Wnt/β-catenin canonical and Wnt non-canonical) and SHH signaling pathways and their connectivity patterns in interaction and signaling networks. Further, the aim was to decipher underlying mechanistic patterns that may be involved in a more specific way and to generate a ranked list of genes that can be used as markers or drug targets. These studies predict that Wnt pathway plays a relatively more pro-active role than the SHH pathway in GBM. Further, CTNNB1, CSNK1A1, and Gli2 proteins may act as key drug targets common to these pathways. While CTNNB1 is a widely studied molecule in the context of GBM, the likely roles of CSNK1A1 and Gli2 are found to be relatively novel. It is surmised that Gli2 may be antagonistic to CSNK1A1, preventing the phosphorylation of CTNNB1 and SMO proteins in Wnt and SHH signaling pathway, respectively, by CSNK1A1, and thereby, aberrant activation. New insights into the possible behavior of these pathway molecules relative to each other in GBM reveal some key interesting patterns.
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Martinez-Høyer, Sergio, Angela Mo, Deborah Deng, Jihong Jiang, Rod Docking, Jenny Li, Simon Chan, et al. "Resistance to Lenalidomide in Del(5q) MDS Is Mediated By Inhibition of Drug-Induced Megakaryocytic Differentiation." Blood 132, Supplement 1 (November 29, 2018): 176. http://dx.doi.org/10.1182/blood-2018-176.
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Abstract The immunomodulatory drug lenalidomide (LEN) is the treatment of choice for del(5q) MDS patients. LEN has been shown to trigger the specific degradation of CSNK1A1 and IKZF1 proteins after binding the E3-ligase substrate adaptor CRBN. When brought below a certain expression threshold, CSNK1A1 deficiency activates a p53-dependent apoptotic response. Thus, the unique sensitivity of del(5q) cells to LEN is explained by CSNK1A1 haploinsufficiency in del(5q) MDS patients. Despite its efficacy, 50% of LEN-treated patients eventually relapse within an interval of 2-3 years after treatment. Treatment failure is associated to low platelet counts and occurrence of additional mutations, such as TP53. To identify novel genetic determinants of LEN resistance, we have compared whole genome sequencing data of paired samples from six del(5q) patients who have been treated with LEN and eventually became resistant to the treatment. We identified 2 patients with mutations in TP53. The remaining four presented RUNX1 alterations: two patients had protein coding mutations in RUNX1 and two had a significant reduction in RUNX1, but not TP53, transcript levels. As a model of sensitivity, we studied the response to LEN in two human del(5q) cell lines, MDS-L and KG-1a. RUNX1 protein levels are postranscriptionally upregulated upon exposure to LEN, accompanied by increased levels of RUNX1 activity. Deletion of CRBN expression cancelled these effects. RUNX1 overexpression inhibited clonogenic growth and induced apoptosis. We then generated RUNX1 knock-out (KO) clones derived from MDS-L cells using CRISPR/Cas9 system. RUNX1 KO cells presented increased proliferation, increased colony growth and reduced apoptosis in the presence of LEN compared to wild-type (WT) control clones. These results were validated with different shRNAs against RUNX1. Genetic rescue experiments showed that RUNX1 mutants were unable to restore sensitivity to the drug compared to RUNX1 WT. Finally, modeling RUNX1 loss-of-function (LOF) in CSNK1A-depleted human CD34+ cells abrogated the effects of LEN on colony forming cell assays. Thus, RUNX1 function is required for the elimination of del(5q) cells by LEN. To understand the molecular mechanisms underlying the resistant phenotype, we performed RNA-seq on MDS-L cells treated with LEN for 24h. We observed a significant upregulation of Platelet specific genes (ITGB3, ITGA2B, VWF, THBD, SELP, TREML1, GATA1) coupled to downregulation of Cell Cycle genes (E2F2, E2F1, MCM5, CDKN1A), suggesting that LEN induces differentiation in to the Megakaryocytic (Meg) lineage. We found a significant upregulation of CD41+/CD61+ double positive cells after LEN exposure in vitro and in vivo, associated to the appearance of multinucleated cells. Importantly, the apoptotic response was associated to the emergence of the differentiating population. At the molecular level, CRBN is required for LEN-induced differentiation. Further downstream we identified IKZF1 degradation as key trigger, as IKZF1 overexpression restrained Meg differentiation and a IKZF1 dominant negative isoform enhanced it. In contrast, CSNK1A overexpression did not alter differentiation after LEN, but did reduce apoptotic induction. Moreover, we identified GATA2 targets enriched in LEN-regulated genes and showed that GATA2 overexpression or downregulation using shRNAs significantly increased or reduced LEN induced differentiation respectively. Finally, gene expression analysis after LEN exposure showed that Meg signatures were not enriched in resistant RUNX1 KO cells compared to WT control. Accordingly, RUNX1 KO cells did not undergo differentiation upon LEN exposure. RUNX1 LOF in CSNK1A-depleted primary human CD34+ cells blocked CFU-Mk growth in LEN treated cells. GATA2 overexpression was unable to restore LEN effects in RUNX1 deficient cells, suggesting a cooperative mechanism between both transcription factors. Luciferase assays using the human CD41 promoter showed that RUNX1 mutants reduced promoter transactivation compared to RUNX1 WT. Remarkably, we observed a similar phenotype for LEN-resistant TP53 KO cells. As a conclusion, our results suggest that GATA2, RUNX1 and TP53 cooperate to drive Meg differentiation after LEN-mediated degradation of IKZF1 protein. Loss of function mutations affecting RUNX1 or TP53 alter the activity of GATA2 transcriptional complex, rendering del(5q) cells unresponsive to LEN. Disclosures Platzbecker: Celgene: Research Funding.
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Vinall, M., and E. C. Fink. "Activity of Lenalidomide in MDS Tied to Degradation of CSNK1A1." MD Conference Express 14, no. 55 (December 1, 2014): 7–8. http://dx.doi.org/10.1177/1559897714568636.
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Sauta, Elisabetta, Francesca Reggiani, Federica Torricelli, Eleonora Zanetti, Elena Tagliavini, Giacomo Santandrea, Giulia Gobbi, et al. "CSNK1A1, KDM2A, and LTB4R2 Are New Druggable Vulnerabilities in Lung Cancer." Cancers 13, no. 14 (July 12, 2021): 3477. http://dx.doi.org/10.3390/cancers13143477.
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Lung cancer is the leading cause of cancer-related human death. It is a heterogeneous disease, classified in two main histotypes, small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC), which is further subdivided into squamous-cell carcinoma (SCC) and adenocarcinoma (AD) subtypes. Despite the introduction of innovative therapeutics, mainly designed to specifically treat AD patients, the prognosis of lung cancer remains poor. In particular, available treatments for SCLC and SCC patients are currently limited to platinum-based chemotherapy and immune checkpoint inhibitors. In this work, we used an integrative approach to identify novel vulnerabilities in lung cancer. First, we compared the data from a CRISPR/Cas9 dependency screening performed in our laboratory with Cancer Dependency Map Project data, essentiality comprising information on 73 lung cancer cell lines. Next, to identify relevant therapeutic targets, we integrated dependency data with pharmacological data and TCGA gene expression information. Through this analysis, we identified CSNK1A1, KDM2A, and LTB4R2 as relevant druggable essentiality genes in lung cancer. We validated the antiproliferative effect of genetic or pharmacological inhibition of these genes in two lung cancer cell lines. Overall, our results identified new vulnerabilities associated with different lung cancer histotypes, laying the basis for the development of new therapeutic strategies.
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Pellagatti, Andrea, and Jacqueline Boultwood. "RECENT ADVANCES IN THE 5Q- SYNDROME." Mediterranean Journal of Hematology and Infectious Diseases 7 (May 20, 2015): e2015037. http://dx.doi.org/10.4084/mjhid.2015.037.
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The 5q- syndrome is the most distinct of the myelodysplastic syndromes (MDS) and patients with this disorder have a deletion of chromosome 5q [del(5q)] as the sole karyotypic abnormality. Several genes mapping to the commonly deleted region of the 5q- syndrome have been implicated in disease pathogenesis in recent years. Haploinsufficiency of the ribosomal gene RPS14 has been shown to cause the erythroid defect in the 5q- syndrome. Loss of the microRNA genes miR-145 and miR-146a has been associated with the thrombocytosis observed in 5q- syndrome patients. Haploinsufficiency of CSNK1A1 leads to hematopoietic stem cell expansion in mice and may play a role in the initial clonal expansion in patients with 5q- syndrome. Moreover, a subset of patients harbor mutation of the remaining CSNK1A1 allele. Mouse models of the 5q- syndrome, which recapitulate the key features of the human disease, indicate that a p53-dependent mechanism underlies the pathophysiology of this disorder. Importantly, activation of p53 has been demonstrated in the human 5q- syndrome. Recurrent TP53 mutations have been associated with an increased risk of disease evolution and with decreased response to the drug lenalidomide in del(5q) MDS patients. Potential new therapeutic agents for del(5q) MDS include the translation enhancer L-leucine.
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Bello, Erica, Andrea Pellagatti, Jacqueline Shaw, Cristina Mecucci, Rajko Kušec, Sally Killick, Aristoteles Giagounidis, et al. "CSNK1A1 mutations and gene expression analysis in myelodysplastic syndromes with del(5q)." British Journal of Haematology 171, no. 2 (June 18, 2015): 210–14. http://dx.doi.org/10.1111/bjh.13563.
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Bao, Xiaomin, Zurab Siprashvili, Brian J. Zarnegar, Rajani M. Shenoy, Eon J. Rios, Natalie Nady, Kun Qu, et al. "CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue." Developmental Cell 43, no. 2 (October 2017): 227–39. http://dx.doi.org/10.1016/j.devcel.2017.08.021.
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Liu, Guanzheng, Huan Li, Wanhong Zhang, Jiefeng Yu, Xu Zhang, Runqiu Wu, Mingshan Niu, Xuejiao Liu, and Rutong Yu. "Csnk1a1 inhibition modulates the inflammatory secretome and enhances response to radiotherapy in glioma." Journal of Cellular and Molecular Medicine 25, no. 15 (July 3, 2021): 7395–406. http://dx.doi.org/10.1111/jcmm.16767.
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Smith, Alexander E., Austin G. Kulasekararaj, Jie Jiang, Syed Mian, Azim Mohamedali, Joop Gaken, Robin Ireland, Barbara Czepulkowski, Steven Best, and Ghulam J. Mufti. "CSNK1A1 mutations and isolated del(5q) abnormality in myelodysplastic syndrome: a retrospective mutational analysis." Lancet Haematology 2, no. 5 (May 2015): e212-e221. http://dx.doi.org/10.1016/s2352-3026(15)00050-2.
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Adema, Vera, Laura Palomo, Cassandra M. Kerr, Wencke Walter, Bartlomiej Przychodzen, Stephan Hutter, Thomas Laframboise, et al. "Molecular Dissection of Del(5q): Distinction between Primary and Secondary Del(5q) and Pathogenetic Implications." Blood 134, Supplement_1 (November 13, 2019): 4221. http://dx.doi.org/10.1182/blood-2019-129292.
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Del(5q) is the most common cytogenetic (CG) alteration in myeloid neoplasia (MN), and solo defines the 5q- syndrome. Despite significant progress in understanding the disease mechanisms resulting from del(5q), the pathogenesis behind this lesion, in particular its effect on leukemogenesis, is still not clear. The absence of corresponding somatic LOH in the del(5q) region suggests that the haploinsufficiency (HI) resulting from the deletion might be the key pathogenic factor. However, none of the investigated HI genes located on del(5q) can explain the 5q related growth advantage/transformation. High molecular diversity including somatic mutations in the retained allele, additional CG abnormalities, epigenetic factors (loss/gain of silencing), and LOH for germ line (GL) protective alleles may preclude the identification of the pathogenically essential lesions. We revisit the genomics of del(5q) by taking advantage of a large cohort of patients with molecular (WES, WGS, RNAseq) and clinical annotation. We analyzed a total of 400 samples (388 patients) with del(5q) and 825 diploid patients with MN. Patients were subgrouped into isolated del(5q) (iso-del5q; 49%) and del(5q) with additional lesions referred to as compound del(5q) (comp-del5q). Availability of paired GL WES results allowed us to reconstruct clonal hierarchy using precise bioanalytic allelic exclusion methods. Studies have postulated that del(5q) is a founder event; we now demonstrate that 52% of iso-del5q patients did have a dominant del(5q) event, but in 56% of comp-del5q and 28% of iso-del5q, del(5q) was subclonal. Co-dominant del(5q) with somatic mutations were also found (iso-del5q: 20% vs. comp-del5q: 11%). When del(5q) was dominant, patients had fewer associated mutations, while cases with secondary del(5q) had a poor prognosis due to ancestral TP53 mutations (MT) and accumulation of chromosomal breaks. We then focused on the expression level: 405 genes on 5q were interrogated, 188 within q14q34 (CDR-1: 41; CDR-2: 55). We defined HI as expression <25th %tile of the diploid expression. CSNK1A1 was deleted in 90% and HI in 77% of del(5q), whereas RPS14 was deleted in 89% but HI in 39% of del(5q) cases. Applying a more stringent definition (<68% of diploid), the most consistently HI genes were SIL1 in 61%, H2AFY in 58%, and CTNNA1 in 49% of cases vs. <5% of diploid cases. By this criterion, RPS14, ACSL6 and TGFBI were also HI in 19%, 17% and 16% of diploid cases. Del(5q) HI genes showed an enrichment of 49x in β-catenin phosphorylation cascade genes (P<.0001), 25x in Wnt signaling (P=.001) and 5x in cell cycle genes (P<.0001). When the entire profile was examined, TP53 and apoptotic genes also showed enrichment in upregulation (both P<.0001). We also genotyped del(5q) and a control diploid cohort for somatic mutations. Within the 5q CDR APC, RAD50, and CSNK1A1 were most frequently mutated (all hemizygous), particularlly in iso-del5q. No canonical DDX41 frame shift mutations (GL) or somatic mutations occurred in its ATP binding domains were found. However, there were DDX41MT (n=2) that coincided with del(5q) and one patient coincided with the CDR. Del(5q) patients had a distinct mutational profile of co-associated lesions with a higher frequency of TP53MT (P<.0001) and a significantly lower frequency of SF3B1, ASXL1, TET2, JAK2, SETBP1, U2AF1 and SRSF2 mutations (all P<.01) than diploid patients. TP53MT were enriched in comp-del5q in cases that frequently also demonstrated -7/7q- and 17p-. CSNK1A1 and TP53 are the two most common mutations in del(5q) patients. CSNK1A1MT were co-mutated with TP53 in only 15% of patients and CSNK1A1 HI did not enrich for TP53MT. Expression of p21 (a TP53 activation marker) was up-regulated in del(5q) except for cases with biallelic TP53 inactivation. RPS14 was HI in a fraction of del(5q) patients. Patients with the RPS14 deleted locus were more likely that those with HI to have an increase in p21 expression (P<.0001) but only in patients with advanced disease. In sum, our analysis of a comprehensive compendium of del(5q) genomics revises previous assumptions (del(5q) is not a uniform founder lesion, and the heterogeneity HI of genes across patients), discovers new HI candidate genes and precisely describes molecular relationships (e.g., del(5q) with TP53) and generated a minimalistic expression signature of del(5q). Disclosures Walter: MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Díez-Campelo:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Nazha:Jazz Pharmacutical: Research Funding; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Daiichi Sankyo: Consultancy. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.
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Carreras Puigvert, J., L. von Stechow, R. Siddappa, A. Pines, M. Bahjat, L. C. J. M. Haazen, J. V. Olsen, et al. "Systems Biology Approach Identifies the Kinase Csnk1a1 as a Regulator of the DNA Damage Response in Embryonic Stem Cells." Science Signaling 6, no. 259 (January 22, 2013): ra5. http://dx.doi.org/10.1126/scisignal.2003208.
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Chesnais, V., M. Passet, S. Bondu, A. Toma, P. Fenaux, F. Dreyfus, M. Fontenay, O. Kosmider, and GFM. "159 CSNK1A1 IS NORMALLY EXPRESSED AND UNMUTATED IN MDS PATIENTS WITHOUT DEL(5Q) BEFORE AND UNDER TREATMENT WITH LENALIDOMIDE." Leukemia Research 39 (April 2015): S81. http://dx.doi.org/10.1016/s0145-2126(15)30160-0.
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Demirci, U., S. Örenay Boyacıoğlu, E. Kasap, F. Bilgiç, E. Gerçeker, H. Yıldırım, A. Baykan, E. Ellidokuz, M. Yüceyar, and M. Korkmaz. "P-014 Are RHOA, CSNK1A1, DVL2, FZD8 and LRP5 Genes Novel Biomarkers in the conversion from Intestinal Metaplasia to Gastric Cancer?" Annals of Oncology 27 (June 2016): ii4. http://dx.doi.org/10.1093/annonc/mdw199.14.
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Ribezzo, Flavia, Inge A. M. Snoeren, Susanne Ziegler, Jacques Stoelben, Patricia A. Olofsen, Almira Henic, Monica Ventura Ferreira, et al. "Rps14, Csnk1a1 and miRNA145/miRNA146a deficiency cooperate in the clinical phenotype and activation of the innate immune system in the 5q- syndrome." Leukemia 33, no. 7 (January 16, 2019): 1759–72. http://dx.doi.org/10.1038/s41375-018-0350-3.
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Theriot, Corey A., Patricia Chevez-Barrios, Thomas Loughlin, Afshin Beheshti, Nathaniel D. Mercaldo, and Susana B. Zanello. "The Impact of Hindlimb Suspension on the Rat Eye: A Molecular and Histological Analysis of the Retina." Gravitational and Space Research 9, no. 1 (January 1, 2021): 86–103. http://dx.doi.org/10.2478/gsr-2021-0007.
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Abstract The Spaceflight Associated Neuro-ocular Syndrome (SANS) is hypothesized to be associated with microgravity-induced fluid shifts. There is a need for an animal model of SANS to investigate its pathophysiology. We used the rat hindlimb suspension (HS) model to examine the relationship between the assumed cephalad fluid shifts, intraocular (IOP) pressure and the molecular responses in the retina to the prolonged change in body posture. Long evans rats were subjected to HS up to 90 days. Animals completing 90-day suspension were further studied for recovery periods up to 90 additional days in normal posture. With respect to baseline, the average IOP increase in HS animals and the rate of change varied by cohort. Transcriptomics evidence supported a response to HS in the rat retina that was affected by age and sex. Several molecular networks suggested stress imposed by HS affected the retinal vasculature, oxidative and inflammation status, pigmented epithelium and glia. The CSNK1A1-TP53 pathway was implicated in the response in all cohorts. Sex-specific genes were involved in cytoprotection and may explain sex-dependent vulnerabilities to certain eye diseases. These results support the hypothesis that changes in the biology of the retina subjected to simulated microgravity involve both the neural and vascular retina.
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Adema, Vera, Laura Palomo, Francisco Fuster-Tormo, Rocío Benito, Rocio Salgado, Esperanza Such, Olivier Kosmider, et al. "Comparison of the Molecular Spectrum of Lenalidomide-Treated Myelodysplastic Syndrome with and without Del(5q)." Blood 128, no. 22 (December 2, 2016): 3172. http://dx.doi.org/10.1182/blood.v128.22.3172.3172.
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Abstract Background: Lenalidomide (LEN) is an immunomodulatory drug which binds cereblon through a glutarimide ring modulating the substrate specificity of CRL4CRBNE3 ubiquitin ligase complex, resulting in the proteosomal degradation of specific disease-related proteins. LEN is approved for the treatment of RBC transfusion-dependent (TD) low and int-1 risk MDS patients with del(5q), 70% of whom reach RBC transfusion-independence (TI) and 50% complete cytogenetic remission. It is also under investigation in RBC -TD low and int-1 risk MDS without del(5q) resistant to erythropoietin stimulating agents and with 20-30% of patients reaching RBC-TI. Herein we aimed to study whether molecular mutations in MDS patients with and without del(5q) influenced the response to LEN treatment. Methods: We collected 95 MDS patients treated with LEN, 72 with del(5q) and 23 without del(5q) (23/23: normal karyotype, presence of ringed sideroblasts and SF3B1MUT). Retrospective clinical information was available for 65 patients. To characterize the mutational spectrum of patients with del(5q) and non del(5q), we combined results from multi amplicon targeted sequencing Ion Torrent (44 cases) and from captured-based targeted deep sequencing (51 cases). The Ion Torrent panel included 39 of the most frequently mutated genes in MDS (ASXL1, BCOR, BRAF, CBL, CDKN2A, CEBPA, DNMT3A, ETV6, EZH2, FLT3, GNAS, IDH1, IDH2, JAK2, KIT, KRAS, LUC7L2, MPL, NF1, NPM1, NRAS, PHF6, PTPN11, RAD21, RPS14, RUNX1, SETBP1, SF1, SF3A1, SF3B1, SMC3, SPARC, SRSF2, STAG2, TET2, TP53, U2AF1, WT1, ZRSR2). The Ion Torrent panel was then extended for the captured-base sequencing and updated with the addition of 43 genes including BCORL1, CALR, CSNK1A1 and KDM6A. The average depth per gene was 780x per sample. Results: Patients with del(5q) vs. non del(5q) had an equal risk distribution (LR: 46/55 vs. 21/22; HR: 9/55 vs. 1/22). We restricted our analyses to LR patients. Median age was 69 yrs (34-90) and M:F ratio was 15:50. A significantly higher median of hemoglobin (Hb) levels were found in del(5q) in comparison to non del(5q) patients (9 g/dL (6-13) vs. 8 g/dL (7-9); P=.001). Molecularly we found that a slightly lower number of mutations occurred in del(5q) [2 mutations (0-6)] compared to the number of mutations in non del(5q) [3 mutations (1-7); P=.001]. WHO 2008 distribution was significantly (P<.001) different between del(5q) and non del(5q) patients, being del(5q) overrepresented by the MDS with isolated del(5q) (74%, 34/46) group while non del(5q) was overrepresented in RARS (67%, 14/21) group. We then compared responders vs. non-responders. LEN median treatment was 10 mo. (3-48 mo.), with an overall follow-up of 4 years (4mo.-10 yrs). As expected, LEN response rate was significantly (P<.001) higher in patients with del(5q) (86%; 25/39) than with non del(5q) (14%; 4/23) patients. Responders showed a significant improvement in Hb levels in comparison to non-responders (N=27 vs. N=32; 9 g/dL (6-12) vs. 8 g/dL (5-10); P=.05), and a lower median number of mutations [3 mutations (1-5)] rather than responders [2 mutations (0-7)]. According to the WHO 2008, responders were significantly (P=.001) grouped in MDS with isolated del(5q) while non-responders were in between RARS (13/29) and RCMD (11/29). We then selected mutated genes present in at least 3 patients. CSNK1A1 (2), BCOR (3), CTCF (3) CUX1 (3), JAK2 (9) KIT (3) and TP53 (11) were restricted to the del(5q) patients. No genes were restricted to non del(5q) group. However, those genes in both groups [del(5q) vs. non del(5q)] were significantly more mutated in non del(5q) group rather than in del(5q) group: ASXL1 (N=6/23 vs. N=4/72; P=.005) and TET2 (N=9/23 vs. N=8/72; P=.002). CSNK1A1 (2) and MECOM (2) genes were restricted to the responders group. CTCF (3), SRSF2 (3), GNAS (2) and IDH2 (2) were only represented in the non-responders group. Genes significantly mutated in non-responders vs. responders were TET2 (N=11/33 vs. N=2/29; P=.011) and TP53 (N=6/33 vs. N=1/29; P=.069). Conclusion: In conclusion, this multicenter study describes that del(5q) and non del(5q) have a different mutational profile although no unifying somatic defect was found. Moreover, non-responders patients had a higher number of mutations and a higher percentage of TET2 and TP53 mutations while responders showed some unique mutations. Disclosures Maciejewski: Celgene: Consultancy, Honoraria, Speakers Bureau; Alexion Pharmaceuticals Inc: Consultancy, Honoraria, Speakers Bureau; Apellis Pharmaceuticals Inc: Membership on an entity's Board of Directors or advisory committees. Fenaux:Celgene, Janssen,Novartis, Astex, Teva: Honoraria, Research Funding. Sole:Celgene: Membership on an entity's Board of Directors or advisory committees.
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Peer, Elisabeth, Sophie Karoline Aichberger, Filip Vilotic, Wolfgang Gruber, Thomas Parigger, Sandra Grund-Gröschke, Dominik Patrick Elmer, et al. "Casein Kinase 1D Encodes a Novel Drug Target in Hedgehog—GLI-Driven Cancers and Tumor-Initiating Cells Resistant to SMO Inhibition." Cancers 13, no. 16 (August 23, 2021): 4227. http://dx.doi.org/10.3390/cancers13164227.
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(1) Background: Aberrant activation of the hedgehog (HH)—GLI pathway in stem-like tumor-initiating cells (TIC) is a frequent oncogenic driver signal in various human malignancies. Remarkable efficacy of anti-HH therapeutics led to the approval of HH inhibitors targeting the key pathway effector smoothened (SMO) in basal cell carcinoma and acute myeloid leukemia. However, frequent development of drug resistance and severe adverse effects of SMO inhibitors pose major challenges that require alternative treatment strategies targeting HH—GLI in TIC downstream of SMO. We therefore investigated members of the casein kinase 1 (CSNK1) family as novel drug targets in HH—GLI-driven malignancies. (2) Methods: We genetically and pharmacologically inhibited CSNK1D in HH-dependent cancer cells displaying either sensitivity or resistance to SMO inhibitors. To address the role of CSNK1D in oncogenic HH signaling and tumor growth and initiation, we quantitatively analyzed HH target gene expression, performed genetic and chemical perturbations of CSNK1D activity, and monitored the oncogenic transformation of TIC in vitro and in vivo using 3D clonogenic tumor spheroid assays and xenograft models. (3) Results: We show that CSNK1D plays a critical role in controlling oncogenic GLI activity downstream of SMO. We provide evidence that inhibition of CSNK1D interferes with oncogenic HH signaling in both SMO inhibitor-sensitive and -resistant tumor settings. Furthermore, genetic and pharmacologic perturbation of CSNK1D decreases the clonogenic growth of GLI-dependent TIC in vitro and in vivo. (4) Conclusions: Pharmacologic targeting of CSNK1D represents a novel therapeutic approach for the treatment of both SMO inhibitor-sensitive and -resistant tumors.
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Hussein, Usama Khamis, Asmaa Gamal Ahmed, Yiping Song, Kyoung Min Kim, Young Jae Moon, Ae-Ri Ahn, Ho Sung Park, et al. "CK2α/CSNK2A1 Induces Resistance to Doxorubicin through SIRT6-Mediated Activation of the DNA Damage Repair Pathway." Cells 10, no. 7 (July 13, 2021): 1770. http://dx.doi.org/10.3390/cells10071770.
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CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas.
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Martinez-Høyer, Sergio, Rod Docking, Simon Chan, Martin Jadersten, Jeremy Parker, and Aly Karsan. "Mechanisms of Resistance to Lenalidomide in Del(5q) Myelodysplastic Syndrome Patients." Blood 126, no. 23 (December 3, 2015): 5228. http://dx.doi.org/10.1182/blood.v126.23.5228.5228.
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Abstract Myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem/progenitor cell malignancies characterized by the presence of dysplastic bone marrow (BM) cells leading to inefficient hematopoiesis in one or more myeloid lineages. The most common chromosomal alteration in MDS, accounting for ~20% of cases, is defined by interstitial deletion of the long arm of chromosome 5, and these cases comprise a distinctive subtype in MDS termed del(5q) . Patients suffering from del(5q) MDS present with anemia, variable neutropenia and thrombocytosis. Patients are blood transfusion dependent, which over time can lead to high mortality due to iron overload. The immunomodulatory drug lenalidomide (LEN) is the treatment of choice for del(5q) patients, achieving transfusion independence and remission in two thirds of treated patients. At the molecular level, LEN cytotoxic activity relies on its binding to the E3-ligase adaptor cereblon (CRBN) selectively leading to CSNK1a protein degradation. Unfortunately, 50% of patients eventually acquire resistance and relapse 2 to 3 years after treatment. Of note, patients at relapse present an increased risk to progress to acute myeloid leukemia. Mutations in the TP53 gene are correlated with resistance to LEN in del(5q) MDS. However, only approximately 20% of patients that become resistant are TP53 mutated. Therefore, there is a medical need to identify drivers of resistance to LEN in del(5q) patients in order to design patient tailored therapies and prevent relapse episodes. To this end, we have collected CD34+ cells from the BM of six del(5q) MDS patients at the time of diagnosis and upon relapse after treatment with LEN and performed whole genome and transcriptome sequencing on these paired samples. By comparing the genome sequencing data at the two time points, we have identified two patients harboring mutations in the TP53 gene: TP53 R273S arises de novo at the resistant stage and TP53 C106Y is existing at diagnosis and expands at relapse. These results are in accordance with previous reports showing strong association of TP53 mutations and resistance to LEN and therefore validate our approach. In addition, we have identified candidate mutations as drivers of the resistant phenotype, which we hypothesize may substitute or cooperate with TP53 mutations, allowing for the malignant del(5q) stem cell survival during LEN treatment and expansion at relapse. Furthermore, RNA-seq data analysis from the paired samples has identified differentially expressed genes shared among all resistant cases and led us to identify novel putative pathways leading to resistance to LEN in del(5q) hematopoietic stem cell. Of note, we did not find any mutation or significant change in the expression of CRBN or CSNK1A1 genes in our cohort of del(5q) MDS patients at relapse, and therefore they do not have a prognostic value for resistance to LEN. The integration of the data obtained in our study will shed light in to the molecular mechanisms leading to resistance to LEN in del(5q) MDS patients and may pave the way for the design of novel and more effective therapies to treat these patients at relapse. Disclosures No relevant conflicts of interest to declare.
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Haferlach, Claudia, Anna Stengel, Manja Meggendorfer, Wolfgang Kern, and Torsten Haferlach. "Impact of 1p Deletions in Myelodysplastic Syndromes and Secondary AML Arising from Myelodysplastic Syndromes." Blood 128, no. 22 (December 2, 2016): 2006. http://dx.doi.org/10.1182/blood.v128.22.2006.2006.
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Background: Deletions in the short arm of chromosome 1 are rare, recurrent abnormalities in Myelodysplastic syndromes (MDS) and are observed as the sole abnormality in 0.2% (Schanz et al. JCO 2012). So far no comprehensive characterization of this subset has been performed. Aim: The aim of this study was to characterize MDS and secondary AML evolving from MDS harboring a 1p deletion with respect to 1) accompanying cytogenetic and molecular genetic abnormalities, 2) the size of the 1p deletion and the minimal deleted region. Patients and Methods: 50 cases with MDS (de novo MDS: n=38, t-MDS: n=8) and secondary AML evolving from MDS (n=4) harboring a 1p deletion were selected for analysis. All cases were evaluated by chromosome banding analysis. From 30 cases sufficient material was available to perform genomic array analysis (SurePrint G3 ISCA CGH+SNP Microarray, Agilent, Waldbronn, Germany) and amplicon sequencing to detect mutations in ASXL1, CBL, CSF3R, CSNK1A1, DNMT3A, ETNK1, ETV6, EZH2, GATA1, IDH1, IDH2, JAK, KIT, KRAS, MPL, NPM1, NRAS, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, and U2AF1. Variants of unknown significance were excluded from statistical analysis. Results: 62% were male and median age was 75 years (range: 35 - 91). The 1p deletion was the sole chromosomal abnormality in 5/50 cases (10%) and was accompanied by one, two and more than two additional aberrations in 12 (24%), 15 (30%), and 18 (36%) cases, respectively. In total 129 chromosome abnormalities were observed in addition to the 1p deletion (median per patient: 2, range: 0-9). Of these only 10 were balanced, while 119 were unbalanced abnormalities leading to gain or loss of chromosomal material. Loss of 1p was most frequently accompanied by del(5q) (n=24; 48%), +8 (n=20; 39%), 7q-/-7 (n=11; 22%), del(17p) (n=5; 10%), and -Y (n=3; 6%). In 15 cases (29%) a duplication of the short arm of chromosome 1 harboring the 1p deletion was observed. Genomic array analyses revealed a median size of the 1p deletion of 25 MB (range: 13-34 MB). A minimal deleted region encountered in all 30 evaluable patients ranged from genomic position 17,872,935 to 24,285,861 encompassing 72 genes (e.g. E2F2, ID3, PAX7, UBR4, ZBTB40) and 10 micro RNAs. One, 2, 3, and 4 mutations were present in 10 (33%), 8 (26%), 5 (17%) and 2 (7%) cases, respectively. No mutations in any of the analyzed genes were observed in 5 cases (17%). Mutations were detected in SF3B1 (16%), TET2 (16%), ASXL1 (13%), DNMT3A (13%), EZH2 (13%), NRAS (13%), SRSF2 (13%), TP53 (13%), JAK2 (10%), KRAS (7%), U2AF1 (7%), CALR (3%), IDH2 (3%), MPL (3%), RUNX1 (3%), and SETBP1 (3%). No mutations were detected in CBL, CSF3R, CSNK1A1, ETNK1, ETV6, GATA1, IDH1, KIT, and NPM1. Compared to published data (Bejar et al. NEJM 2012, Papaemmanuil et al. Blood 2013, Haferlach et al. Leukemia 2014) SF3B1 (20-30%) and TET2 (20-30%) mutations seem to be less frequent and mutations in TP53 (6-8%), EZH2 (5-7%), NRAS (4-5%) and KRAS (1-3%) more frequent in MDS with 1p deletion compared to an unselected MDS cohort. Patients harboring either a 1p deletion as the sole abnormality or a duplication of the deleted chromosome 1 (n=20) had an excellent prognosis (3 year overall survival (OS): 100%), while patients with a 1p deletion accompanied by -7/7q- (n=11) had a very poor outcome (3 year OS: 0%; p<0.001). Patients with 1p deletion and other accompanying cytogenetic abnormalities (n=19) had an intermediate outcome (3 year OS: 34%, p=0.03, p=0.003). Conclusions: 1) Interstitial deletions in the short arm of chromosome 1 are rare recurrent abnormalities in MDS. 2) 5q deletion, +8, -7/7q- are frequently observed in addition to 1p deletion. 3) Both MDS with a 1p deletion as the sole abnormality and MDS with a duplication of deleted chromosome 1 are associated with very favorable outcome. 4) Accompanying abnormalities, especially -7/7q- have a negative impact on outcome. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Stengel:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Etchegaray, Jean-Pierre, Kazuhiko K. Machida, Elizabeth Noton, Cara M. Constance, Robert Dallmann, Marianne N. Di Napoli, Jason P. DeBruyne, et al. "Casein Kinase 1 Delta Regulates the Pace of the Mammalian Circadian Clock." Molecular and Cellular Biology 29, no. 14 (May 4, 2009): 3853–66. http://dx.doi.org/10.1128/mcb.00338-09.
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ABSTRACT Both casein kinase 1 delta (CK1δ) and epsilon (CK1ε) phosphorylate core clock proteins of the mammalian circadian oscillator. To assess the roles of CK1δ and CK1ε in the circadian clock mechanism, we generated mice in which the genes encoding these proteins (Csnk1d and Csnk1e, respectively) could be disrupted using the Cre-loxP system. Cre-mediated excision of the floxed exon 2 from Csnk1d led to in-frame splicing and production of a deletion mutant protein (CK1δΔ2). This product is nonfunctional. Mice homozygous for the allele lacking exon 2 die in the perinatal period, so we generated mice with liver-specific disruption of CK1δ. In livers from these mice, daytime levels of nuclear PER proteins, and PER-CRY-CLOCK complexes were elevated. In vitro, the half-life of PER2 was increased by ∼20%, and the period of PER2::luciferase bioluminescence rhythms was 2 h longer than in controls. Fibroblast cultures from CK1δ-deficient embryos also had long-period rhythms. In contrast, disruption of the gene encoding CK1ε did not alter these circadian endpoints. These results reveal important functional differences between CK1δ and CK1ε: CK1δ plays an unexpectedly important role in maintaining the 24-h circadian cycle length.
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Loukil, Abdelhalim, Chloe Barrington, and Sarah C. Goetz. "A complex of distal appendage–associated kinases linked to human disease regulates ciliary trafficking and stability." Proceedings of the National Academy of Sciences 118, no. 16 (April 12, 2021): e2018740118. http://dx.doi.org/10.1073/pnas.2018740118.
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Cilia biogenesis is a complex, multistep process involving the coordination of multiple cellular trafficking pathways. Despite the importance of ciliogenesis in mediating the cellular response to cues from the microenvironment, we have only a limited understanding of the regulation of cilium assembly. We previously identified Tau tubulin kinase 2 (TTBK2) as a key regulator of ciliogenesis. Here, using CRISPR kinome and biotin identification screening, we identify the CK2 catalytic subunit CSNK2A1 as an important modulator of TTBK2 function in cilia trafficking. Superresolution microscopy reveals that CSNK2A1 is a centrosomal protein concentrated at the mother centriole and associated with the distal appendages. Csnk2a1 mutant cilia are longer than those of control cells, showing instability at the tip associated with ciliary actin cytoskeleton changes. These cilia also abnormally accumulate key cilia assembly and SHH-related proteins. De novo mutations of Csnk2a1 were recently linked to the human genetic disorder Okur-Chung neurodevelopmental syndrome (OCNDS). Consistent with the role of CSNK2A1 in cilium stability, we find that expression of OCNDS-associated Csnk2a1 variants in wild-type cells causes ciliary structural defects. Our findings provide insights into mechanisms involved in ciliary length regulation, trafficking, and stability that in turn shed light on the significance of cilia instability in human disease.
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Adema, Vera, Cassandra M. Kerr, Wencke Walter, Stephan Hutter, Yasunobu Nagata, Hassan Awada, Sunisa Kongkiatkamon, et al. "Can Monosomy 7 be Targeted By Next Generation Cereblon-Modulating Agents?" Blood 134, Supplement_1 (November 13, 2019): 1270. http://dx.doi.org/10.1182/blood-2019-128967.
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Genomic advances have initiated a new era of precision oncology. Targeted therapeutics can rationally select potentially responsive patient populations and exclude resistant patients based on molecular mechanisms of action. The application of immunomodulatory drugs (IMiDs) evolved from unselective usage to the identification of del(5q) as a target, which then led to mechanistic clues and clarification of its mode of action. Lenalidomide (LEN) has been used in non del(5q) patients with a variable response rate, but the molecular underpinnings for LEN efficacy in this setting are not known. Genomic analyses (Negoro et al., Leukemia 2016) have provided only a marginal improvement in response prediction, suggesting that other factors might be relevant in sensitizing cells to LEN. The effects of LEN are related to its binding affinity to cereblon (CRBN), the substrate adaptor of the CRL4CRBN E3 ubiquitin ligase, a cullin-ring ligase consisting of damaged DNA-binding protein1(DDB1), cullin4a (CUL4A), and regulator of cullins-1 (ROC1). LEN selectively activates CRL4CRBN E3 ubiquitin ligase to selectively degrade CSNK1A1 leading to synthetic lethality in patients with del(5q) that are haploinsufficient (HI) for CSNK1A1. However, LEN and the new generation compounds pomalidomide and iberomide (CC-220) also trigger recruitment and degradation of the zinc finger transcription factors IKAROS (IKZF1, 7p12.2) and AIOLOS (IKZF3, 17p12-q21.1) through CRBN, and therefore promote their proteosomal degradation. The synthetic lethality of these immunomodulator agents relies on expression levels of AIOLOS and IKAROS. Response to those agents depends strictly on low expressions of AIOLOS and IKAROS sensitizing certain cell types (e.g., myeloma). We hypothesized that levels of LEN sensitivity might correlate with expression levels of its targets in selected disease subtypes of myeloid neoplasia (MN). We studied a large cohort of patients with MN (n=3,328) and we identified 122 patients with -7 and 194 patients with del(7q). We noted that for those cases with informative RNA-seq expression, IKAROS exhibited haploinsufficient (HI) mRNA levels in 67% of patients with -7 and 40% in del(7q), as defined based on levels <25%tile of the diploid expression of cases (Kerr, ASH 2019). Since IKAROS is described to be a target of iberomide, we hypothesized that monosomy 7 (-7) but not del(7q) could selectively benefit from this agent, analogous to LEN in del(5q). Consistent with this proposition we further selected 160 hematopoietic cancer cells with available IKZF1 CNV status in a publicly available database of cell drug sensitivity (cancerrx). For all cell lines, the anti-proliferative effect of LEN was described. Cells with monosomy of IKZF1 (CNV=1) had an increased sensitivity to LEN as their IC50 was lower than compared to that of cells with IKZF1 with CNV ≥ 2 (6.1μM vs. 24.3μM). To further validate this prediction, we revisited the responsiveness to LEN (defined by Negoro et al., Leukemia 2016) of non-del(5q) MDS patients (n=79) showing an ORR of 40%. By focusing on patients with alterations in chr7 we identified 10 patients with MDS and high or very high International Prognosis Scoring System-Revised (IPSS-R) risk [6 patients with -7 and 4 patients with del(7q)]. In this cohort LEN response was assessed at 3 and 6 months; 4 out 6 patients with -7 responded to LEN, while del(7q) patients were all refractory (n=4). Responding monosomy 7 patients with complete bone marrow response (n=3) received 10 or 50mg doses of LEN (2 patients had a complex karyotype and 1 had isolated -7). The remaining responding patient had a partial response with hematological improvement. Interestingly, this patients was treated with a 5mg dose of LEN and had a TP53 mutation. In the other 2 patients: one with -7, LEN was discontinued because of pancytopenia associated with treatment, while in the other one -7 could not be confirmed by FISH. In the group of del(7q) patients, complex karyotypes and the presence of del(5q) in 2 did not predict for better response. Our preliminary results suggest that selective application of new generation IMiDS targeting IKAROS have clinical potential in patients with -7. Supportive data from in vitro cellular models will be comprehensively presented. Disclosures Walter: MLL Munich Leukemia Laboratory: Employment. Hutter:MLL Munich Leukemia Laboratory: Employment. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Nazha:Tolero, Karyopharma: Honoraria; Incyte: Speakers Bureau; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Daiichi Sankyo: Consultancy; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.
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Hu, Y., W. Song, D. Cirstea, D. Lu, N. C. Munshi, and K. C. Anderson. "CSNK1α1 mediates malignant plasma cell survival." Leukemia 29, no. 2 (June 25, 2014): 474–82. http://dx.doi.org/10.1038/leu.2014.202.
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Wu, Ruo-hao, Wen-ting Tang, Kun-yin Qiu, Xiao-juan Li, Dan-xia Tang, Zhe Meng, and Zhan-wen He. "Identification of novel CSNK2A1 variants and the genotype–phenotype relationship in patients with Okur–Chung neurodevelopmental syndrome: a case report and systematic literature review." Journal of International Medical Research 49, no. 5 (May 2021): 030006052110170. http://dx.doi.org/10.1177/03000605211017063.
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De novo germline variants of the casein kinase 2α subunit (CK2α) gene ( CSNK2A1) have been reported in individuals with the congenital neuropsychiatric disorder Okur–Chung neurodevelopmental syndrome (OCNS). Here, we report on two unrelated children with OCNS and review the literature to explore the genotype–phenotype relationship in OCNS. Both children showed facial dysmorphism, growth retardation, and neuropsychiatric disorders. Using whole-exome sequencing, we identified two novel de novo CSNK2A1 variants: c.479A>G p.(H160R) and c.238C>T p.(R80C). A search of the literature identified 12 studies that provided information on 35 CSNK2A1 variants in various protein-coding regions of CK2α. By quantitatively analyzing data related to these CSNK2A1 variants and their corresponding phenotypes, we showed for the first time that mutations in protein-coding CK2α regions appear to influence the phenotypic spectrum of OCNS. Mutations altering the ATP/GTP-binding loop were more likely to cause the widest range of phenotypes. Therefore, any assessment of clinical spectra for this disorder should be extremely thorough. This study not only expands the mutational spectrum of OCNS, but also provides a comprehensive overview to improve our understanding of the genotype–phenotype relationship in OCNS.
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Panagiota, Victoria, Manja Meggendorfer, Anne Sophie Kubasch, Razif Gabdoulline, Jan Krönke, Rabia Shahswar, Anna Mies, et al. "The Role of PPM1D Mutations in Lenalidomide Resistance and Progression in Patients with MDS and Deletion of Chromosome 5q." Blood 132, Supplement 1 (November 29, 2018): 4360. http://dx.doi.org/10.1182/blood-2018-99-114026.
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Abstract Background: PPM1D is a serine/threonine phosphatase that inactivates p53 tumor suppressor pathway. Recently, PPM1D mutations have been described in clonal hematopoiesis and are more frequently found in therapy-related MDS than in primary MDS (15% vs. 3%). Del(5q), is the most prevalent cytogenetic abnormality in MDS. A high proportion of MDS del(5q) patients respond to lenalidomide, but almost 40% of them progress to AML. Scharenberg et al. identified recurrent mutations in a limited number of genes i.e. TP53, RUNX1, and TET2 in a longitudinal cohort of 35 MDS del(5q) patients that progressed to AML. The clinical impact and occurrence of PPM1D mutations in MDS del(5q) patients remains unknown. Aim: To determine the clinical impact of PPM1D mutations in MDS del (5q) patients on lenalidomide resistance and AML progression. Methods: We studied a cohort of 243 patients with MDS or AML following MDS and 5q deletion diagnosed according to the 2008 WHO classification. Patients were cytogenetically characterized by chromosome banding analysis and followed for disease progression, treatment and survival. From 22 del(5q) patients treated with lenalidomide, follow-up (FU) material was available before and after treatment. Molecular analysis for mutations in all 6 exons of PPM1D was performed by Sanger and/or a next-generation sequencing panel covering mutations in 46 genes frequently mutated in MDS, including TP53 and CSNK1A1. Results: At the time of diagnosis 14 PPM1D mutations were detected in 13 of 243 (5.3%) MDS patients with del(5q), 12 of which were found in the previously described hotspot region of PPM1D between amino acids 427 and 542. Six patients had nonsense mutations, 3 patients had frameshift mutations (one patient with 2 frameshift mutations), and 4 patients had missense mutations. TP53 mutations were found in 34 of 243 (14%) MDS patients with del(5q). Three TP53 mutated patients, two with complex karyotype, carried an additional PPM1D mutation. Co-occurrence of PPM1D and CSNK1A1 mutations was not observed in any patient. In total, 71 of 243 patients were treated with lenalidomide and had available information about treatment response. Eleven patients (15.5%) did not respond to lenalidomide and 17 patients (24%) progressed to AML. Nine of 71 (12.6%) patients were TP53 (n=5, 7%) or PPM1D mutated (n=4, 5.6%). For 22 of 71 patients who either achieved a complete remission (n=5), developed resistance to lenalidomide followed by MDS progression (n=7) or AML transformation (n=10), FU samples were available before and after lenalidomide treatment. Of the 5 patients with complete remission 4 patients displayed no mutations, while 1 patient was PPM1D- and ASXL1-mutated with a variant allele frequency (VAF) of 27.6% and 12.1%, respectively, prior to lenalidomide treatment. After 76 months on lenalidomide, both mutations had disappeared. Of the 17 patients with lenalidomide resistance/AML progression, 5 patients (29.4%) carried mutations either in PPM1D (n=2) or in TP53 (n=3) prior to lenalidomide treatment, with a mean VAF of 15.3% and 13.5%, respectively. The 2 PPM1D-mutated patients progressed to AML 59.4 and 79.6 months after diagnosis. None of the 3 initially TP53-mutated patients progressed to AML. All 3 TP53-mutated patients co-expressed SF3B1 mutations. At the time of lenalidomide resistance/AML progression, we observed 2 known and 1 novel PPM1D mutation in a patient previously wildtype for PPM1D and TP53, 3 known and 6 novel TP53 mutations in 5 patients previously wildtype for PPM1D and TP53, and 1 novel TP53 mutation in a patient who was previously found mutated in PPM1D. Thus, at the time of lenalidomide resistance or AML progression 10 of 17 patients (58.8%) were mutated for PPM1D (n=3, 18%) and/or TP53 (n=9, 53%; 2 of 9 co-expressed PPM1D mutations). At the time of lenalidomide resistance/AML progression, VAF increased from 10.2% to 23.3% for PPM1D and from 4% to 16.9% for TP53 mutations, indicating expansion of the mutated clone under the selective pressure of lenalidomide. Conclusion: PPM1D mutations are recurrently found in MDS del(5q) patients at a frequency of 5.3% and may be coexpressed with TP53 mutations in 5q- MDS/AML cells. Frequency at resistance/AML progression was 18% for PPM1D and 53% for TP53 mutated patients, respectively. Our findings indicate an association of PPM1D mutations in addition to the previously described TP53 mutations with lenalidomide resistance and AML progression. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Krönke:Celgene: Honoraria. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Thiede:Novartis: Honoraria, Research Funding; AgenDix: Other: Ownership. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Koenecke:Amgen: Consultancy; Roche: Consultancy; abbvie: Consultancy; BMS: Consultancy. Sperr:Novartis: Honoraria; Pfizer: Honoraria; Daiichi Sankyo: Honoraria. Valent:Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Platzbecker:Celgene: Research Funding. Heuser:BergenBio: Research Funding; StemLine Therapeutics: Consultancy; Astellas: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Bayer Pharma AG: Consultancy, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Karyopharm: Research Funding; Daiichi Sankyo: Research Funding; Sunesis: Research Funding; Tetralogic: Research Funding.
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Nguyen Hoang, Anh Thu, Kwang-Lae Hoe, and Sook-Jeong Lee. "CSNK1G2 differently sensitizes tamoxifen-induced decrease in PI3K/AKT/mTOR/S6K and ERK signaling according to the estrogen receptor existence in breast cancer cells." PLOS ONE 16, no. 4 (April 16, 2021): e0246264. http://dx.doi.org/10.1371/journal.pone.0246264.
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Tamoxifen (TAM) is a selective estrogen receptor modulator used for breast cancer patients. Prolonged use of tamoxifen is not recommended for some patients. In this study, we aimed to identify molecular targets sensitive to TAM using a genome-wide gene deletion library screening of fission yeast heterozygous mutants. From the screening, casein kinase 1 gamma 2 (CSNK1G2), a serine-/threonine protein kinase, was the most sensitive target to TAM with a significant cytotoxicity in estrogen receptor-positive (ER+) breast cancer cells but with only a slight toxicity in the case of ER- cells. In addition, tumor sphere formation and expression of breast stem cell marker genes such as CD44/CD2 were greatly inhibited by CSNK1G2 knockdown in ER+ breast cancer cells. Consistently, CSNK1G2 altered ERα activity via phosphorylation, specifically at serine (Ser)167, as well as the regulation of estrogen-responsive element (ERE) of estrogen-responsive genes such as CTSD and GREB1. However, ERα silencing almost completely blocked CSNK1G2-induced TAM sensitivity. In ER+ breast cancer cells, combined treatment with TAM and CSNK1G2 knockdown further enhanced the TAM-mediated decrease in phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)/ribosomal protein S6 kinase (S6K) signaling but not extracellular signal-regulated kinase (ERK) signaling. Inversely, in ER- cells treated with TAM, only ERK and PI3K signaling was altered by CSNK1G2 knockdown. The CK1 inhibitor, D4476, partly mimicked the CSNK1G2 knockdown effect in ER+ breast cancer cells, but with a broader repression ranging from PI3K/AKT/mTOR/S6K to ERK signaling. Collectively, these results suggest that CSNK1G2 plays a key role in sensitizing TAM toxicity in ER+ and ER- breast cancer cells via differently regulating PI3K/AKT/mTOR/S6K and ERK signaling.
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Fuchs, Ota. "Treatment of Lymphoid and Myeloid Malignancies by Immunomodulatory Drugs." Cardiovascular & Hematological Disorders-Drug Targets 19, no. 1 (January 28, 2019): 51–78. http://dx.doi.org/10.2174/1871529x18666180522073855.
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Thalidomide and its derivatives (lenalidomide, pomalidomide, avadomide, iberdomide hydrochoride, CC-885 and CC-90009) form the family of immunomodulatory drugs (IMiDs). Lenalidomide (CC5013, Revlimid®) was approved by the US FDA and the EMA for the treatment of multiple myeloma (MM) patients, low or intermediate-1 risk transfusion-dependent myelodysplastic syndrome (MDS) with chromosome 5q deletion [del(5q)] and relapsed and/or refractory mantle cell lymphoma following bortezomib. Lenalidomide has also been studied in clinical trials and has shown promising activity in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Lenalidomide has anti-inflammatory effects and inhibits angiogenesis. Pomalidomide (CC4047, Imnovid® [EU], Pomalyst® [USA]) was approved for advanced MM insensitive to bortezomib and lenalidomide. Other IMiDs are in phases 1 and 2 of clinical trials. Cereblon (CRBN) seems to have an important role in IMiDs action in both lymphoid and myeloid hematological malignancies. Cereblon acts as the substrate receptor of a cullin-4 really interesting new gene (RING) E3 ubiquitin ligase CRL4CRBN. This E3 ubiquitin ligase in the absence of lenalidomide ubiquitinates CRBN itself and the other components of CRL4CRBN complex. Presence of lenalidomide changes specificity of CRL4CRBN which ubiquitinates two transcription factors, IKZF1 (Ikaros) and IKZF3 (Aiolos), and casein kinase 1α (CK1α) and marks them for degradation in proteasomes. Both these transcription factors (IKZF1 and IKZF3) stimulate proliferation of MM cells and inhibit T cells. Low CRBN level was connected with insensitivity of MM cells to lenalidomide. Lenalidomide decreases expression of protein argonaute-2, which binds to cereblon. Argonaute-2 seems to be an important drug target against IMiDs resistance in MM cells. Lenalidomide decreases also basigin and monocarboxylate transporter 1 in MM cells. MM cells with low expression of Ikaros, Aiolos and basigin are more sensitive to lenalidomide treatment. The CK1α gene (CSNK1A1) is located on 5q32 in commonly deleted region (CDR) in del(5q) MDS. Inhibition of CK1α sensitizes del(5q) MDS cells to lenalidomide. CK1α mediates also survival of malignant plasma cells in MM. Though, inhibition of CK1α is a potential novel therapy not only in del(5q) MDS but also in MM. High level of full length CRBN mRNA in mononuclear cells of bone marrow and of peripheral blood seems to be necessary for successful therapy of del(5q) MDS with lenalidomide. While transfusion independence (TI) after lenalidomide treatment is more than 60% in MDS patients with del(5q), only 25% TI and substantially shorter duration of response with occurrence of neutropenia and thrombocytopenia were achieved in lower risk MDS patients with normal karyotype treated with lenalidomide. Shortage of the biomarkers for lenalidomide response in these MDS patients is the main problem up to now.
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Pellagatti, Andrea, Aristotle Giagounidis, Sally Killick, Lisa J. Campbell, Vicki Wraight, Cordelia F. Langford, Carrie Fidler, et al. "Expression Profiling of CD34+ Cells in Patients with Myelodysplastic Syndromes with and without a del(5q)." Blood 104, no. 11 (November 16, 2004): 2363. http://dx.doi.org/10.1182/blood.v104.11.2363.2363.
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Abstract The myelodysplastic syndromes (MDS) are a heterogeneous group of haematopoietic malignancies, characterized by blood cytopenias, ineffective hematopoiesis and hypercellular bone marrow. MDS are believed to arise from the malignant transformation of a hematopoietic stem cell. We have used Affymetrix microarray technology to determine gene expression profiles in bone marrow CD34+ cells of 17 MDS patients and 6 healthy controls. Nine patients with RA and 8 patients with RAEB were included in the study. Eleven of 17 patients had a del(5q). CD34+ cells were isolated from bone marrow samples of MDS patients and controls using MACS magnetic cell separation columns (purity greater than 85%). Extracted total RNA was amplified using the Two-Cycle Target Labelling and Control Reagent package (Affymetrix). Biotin-labelled fragmented cRNA was hybridized to GeneChip Human Genome U133 Plus 2.0 arrays (Affymetrix), covering over 47,000 transcripts representing 39,000 human genes. Cell intensity calculation and scaling was performed using GeneChip Operating Software (GCOS) and data analysis using GeneSpring 6.2. Genes up-regulated by >2 fold in the majority of MDS patients include IFITM1, an interferon-inducible protein implicated in the control of cell growth, and KANGAI1, a metastasis suppressor gene. IFITM1 was up-regulated in 15 of 17 MDS patients. Up-regulation of DLK1, previously reported in MDS, was confirmed in 8 of 17 MDS patients. Genes down-regulated by >2 fold in the majority of MDS patients include FOSB (a transcription factor which regulates cell proliferation and differentiation), COX2 (anti-apoptotic, promotes cell survival), Gravin/AKAP12 (a putative tumor suppressor gene), CD24 and MME. FOSB was down-regulated in 16 of 17 MDS patients. The results for several genes have been confirmed by real-time quantitative PCR (TaqMan). MDS patients with a del(5q) could be discriminated from those without a del(5q), using a set of 12 genes obtained applying a parametric t-test with multiple testing correction (P<0.01). Five of the 12 genes (DCP2, HTGN29, ANKHD1, CSNK1A1 and RBM22) mapped to chromosome 5q and their expression levels were lower in MDS patients with del(5q) than those without del(5q). Using a parametric t-test with multiple testing correction (P<0.05), 221 genes were found to be significantly different between MDS patients and controls. These 221 genes were ranked by their power to discriminate the two classes. The eight genes with the highest prediction strength were used for leave-one-out cross-validation. Twenty-one of 23 samples (91%) were correctly classified as MDS or control and one was not assigned. This set of genes is being tested on an independent test set to perform class prediction. This study has identified genes differentially expressed in the CD34+ cells of MDS patients that may be important in the molecular pathogenesis of this disorder.
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Schneider, Bjoern, Stefan Nagel, Maren Kaufmann, Hilmar Quentmeier, Yoshinobu Matsuo, Hans G. Drexler, and Roderick A. F. MacLeod. "Analysis of MLL Amplification and 5q Deletions in AML/MDS Cell Lines Identifies Novel Targets." Blood 108, no. 11 (November 16, 2006): 1424. http://dx.doi.org/10.1182/blood.v108.11.1424.1424.
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Abstract Genomic amplifications of the 11q23 region occur in acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) where MLL and a few neighboring genes, notably DDX6, are deemed salient targets. However, the extent to which amp(lified)-MLL and translocated MLL share effector targets remains to be established. Even less is known about the target(s) of deletions affecting the long arm of chromosome 5 (5q-) which reportedly partner amp-MLL. We analyzed three AML/MDS cell lines by cytogenetics (conventional and FISH) in parallel with real time q(uantitative)-PCR at both 11q23 and 5q2 to measure copy number and expression of salient target genes together with putative downstream targets. The cell lines comprised: MOLM-17 (transforming-MDS), SAML-2 (therapy-related AML), and UOC-M1 (AML-M1). All three cell lines exhibited approximately four-fold genomic amplification of 11q23 including MLL and DDX6, while the amplicon extended telomerically to include FLI1 (11q24) and HNT (11q25) in MOLM-17 and UOC-M1 only. Expression, quantified relative to AML/MDS cell lines without MLL rearrangement, revealed that of the genomically amplified genes only MLL was generally overexpressed, namely by 9.5x (MOLM-17), 5.1x (UOC-M1), and 4.6x (SAML-2). In addition to the highest MLL expression, in MOLM-17 FLI1 (3.8x) and DDX6 (2.8x) were significantly upregulated. Expression was also quantified among reputed MLL target genes, and showed that in the three cell lines MEIS1 was upregulated in MOLM-17 only (by 6x), and CDKN2C in all cell lines (by about 2x), while HOXA9 and CDKN1B showed near-normal levels of expression. All three cell lines carried 5q- with a common deleted region at 5q31 extending from 134.2–137.5 Mbp. Of a panel of genes recently identified as 5q- deletion targets (centromere-TIGA1, CAMLG, C5orf15, C5orf14, BRD8, HARS, KIAA0141, CSNK1A1, RBM22-telomere), only C5orf15 (function unknown) and BRD8 (a component of the nua4 histone acetyltransferase complex involved in transcriptional activation) were generally downregulated - to about 0.25x, and about 0.4x normalized expression levels, respectively. Both genes lie within the common deleted region. In summary, we have characterized amp-MLL and 5q- in MOLM-17, the first MDS cell line to be described with these rearrangements, together with two AML cell lines with similar cytogenetic profiles. Our data suggest that MLL is the only clear object of 11q23 amplification hitherto identified and CDKN2C its sole unequivocal target in AML/MDS cell lines. It is possible that MEIS1 is also targeted for activation in specific cell types or disease phases in MDS. These findings also highlight C5orf15 and/or BRD8 as possible leukemogenic accomplices targeted for downregulation in accompanying 5q-. These findings may point to differences in signalling pathways targeted by amp-MLL in AML and MDS.
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Shi, Zhan, Ding Wu, Hao Xu, Ju Yang, and Xiaoqing Sun. "CSNK2A1‐mediated phosphorylation of HMGA2 modulates cisplatin resistance in cervical cancer." FEBS Open Bio 11, no. 8 (July 12, 2021): 2245–55. http://dx.doi.org/10.1002/2211-5463.13228.
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Jiang, Chao, Zhenghong Ma, Guoan Zhang, Xigui Yang, Qin Du, and Weibo Wang. "CSNK2A1 Promotes Gastric Cancer Invasion Through the PI3K-Akt-mTOR Signaling Pathway." Cancer Management and Research Volume 11 (December 2019): 10135–43. http://dx.doi.org/10.2147/cmar.s222620.
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Jiang, Lingong, Huimin Jia, Zhicheng Tang, Xiaofei Zhu, Yangsen Cao, Yin Tang, Haiyan Yu, Jianping Cao, Huojun Zhang, and Shuyu Zhang. "Proteomic Analysis of Radiation-Induced Acute Liver Damage in a Rabbit Model." Dose-Response 17, no. 4 (October 1, 2019): 155932581988950. http://dx.doi.org/10.1177/1559325819889508.
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Radiation-induced liver damage (RILD) has become a limitation in radiotherapy for hepatocellular carcinoma. We established a rabbit model of RILD by CyberKnife. Electron microscopy analysis revealed obvious nuclear atrophy and disposition of fat in the nucleus after irradiation. We then utilized a mass spectrometry-based label-free relative quantitative proteomics approach to compare global proteomic changes of rabbit liver in response to radiation. In total, 2365 proteins were identified, including 338 proteins that were significantly dysregulated between irradiated and nonirradiated liver tissues. These differentially expressed proteins included USP47, POLR2A, CSTB, MCFD2, and CSNK2A1. Real-time polymerase chain reaction confirmed that USP47 and CABLES1 transcripts were significantly higher in irradiated liver tissues, whereas MCFD2 and CSNK2A1 expressions were significantly reduced. In Clusters of Orthologous Groups of proteins analysis, differentially expressed proteins were annotated and divided into 24 categories, including posttranslational modification, protein turnover, and chaperones. Kyoto Encyclopedia of Genes and Genomes analysis revealed that the enriched pathways in dysregulated proteins included the vascular endothelial growth factors (VEGF) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and the adipocytokine signaling pathway. The identification of proteins and pathways is crucial toward elucidating the radiation response process of the liver, which may facilitate the discovery of novel therapeutic targets.
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Schoch, Claudia, Alexander Kohlmann, Wolfgang Kern, Sylvia Merk, Wolfgang Hiddemann, Martin Dugas, Susanne Schnittger, and Torsten Haferlach. "Gene Expression Profiling in AML and MDS Identifies Genes Located on 5q Which Are Consistently Lower Expressed in Cases with 5q Deletion as Compared to Cases with Normal Karyotype." Blood 104, no. 11 (November 16, 2004): 549. http://dx.doi.org/10.1182/blood.v104.11.549.549.
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Abstract Deletions of the long arm of chromosome 5 occur either as the sole karyotype abnormality in MDS and AML or as part of a complex aberrant karyotype. It was the aim of this study to analyze the impact of the 5q deletion on the expression levels of genes located on chromosome 5q in AML and MDS. Therefore, gene expression analysis was performed in 344 AML and MDS cases using Affymetrix U133A+B oligonucleotide microarrays. The following subgroups were analyzed: AML with sole 5q deletion (n=7), AML with complex aberrant karyotype (n=83), MDS with sole 5q deletion (n=9), and MDS with complex aberrant karyotype (n=9). These were compared to 200 AML and 36 MDS with normal karyotype. In total, 1313 probe sets representing 603 genes cover sequences located on the long arm of chromosome 5. Overall a significant lower mean expression of all genes located on the long arm of chromosome 5 was observed in subgroups with 5q deletion in comparison to their respective control groups (for all comparisons, p<0.05). 36 genes showed a significantly lower expression in all comparisons. These genes are involved in a variety of different biological processes such as signal transduction (CSNK1A1, DAMS), cell cycle regulation (HDAC3, PFDN1) and regulation of transcription (CNOT8). In addition we performed class prediction using support vector machines (SVM). In one approach all 6 different subgroups were analyzed as one class each. While AML and MDS with normal karyotype as well as AML with complex aberrant karyotype were correctly predicted with high accuracies (97%, 81%, and 92%, respectively) AML and MDS with 5q- sole and MDS with complex aberrant karyotype were frequently misclassified as AML with complex aberrant karyotype. In a second approach only two classes were defined: all cases with 5q deletion combined vs. all cases without 5q deletion. 102 out of 108 cases (94%) with 5q deletion were identified correctly supporting the fact that a distinct gene expression pattern is associated with 5q deletion in general. Performing SVM only with genes located on the long arm of chromosome 5 also resulted in a correct prediction of 92 of 108 (85%) stressing the importance of the expression of genes located on chromosome 5 for these AML and MDS subtypes. The top 100 differentially expressed probe sets between cases with and without 5q deletion represented 74 different annotated genes of which 23 are located on the long arm of chromosome 5. They are involved in a variety of different biological functions such as DNA repair (POLE, RAD21, RAD23B), regulation of transcription (ZNF75A, AF020591, MLLT3, HOXB6), protein biosynthesis (UPF2, TINP1, RPL12, RPL14, RPL15) cell cycle control (GMNN, CSPG6, PFDN1) and signal transduction (HINT1, STK24, APP, CAMLG). 10 of the top 74 genes associated with 5q deletion were involved in the CMYC-pathway with upregulation of RAD21, RAD23B, GMMN, CSPG6, APP, POLE STK24 and STAG2, and downregulation of ACTA2, and RPL12. Ten other genes out of the 74 top differentially expressed genes were involved in the TP53 pathway with upregulation of H1F0, PTPN11 and TAF2 and downregulation of DF, UBE2D2, EEF1A1, IGBP1, PPP2CA, EIF2S3, and NACA. In conclusion, loss of parts of the long arm of chromosome 5 leads to a lower expression of genes located on the long arm of chromosome 5. A specific pattern of functionally related genes was identified which shows a lower expression in AML and MDS subtypes with 5q deletion.
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Okur, Volkan, Megan T. Cho, Lindsay Henderson, Kyle Retterer, Michael Schneider, Shannon Sattler, Dmitriy Niyazov, et al. "De novo mutations in CSNK2A1 are associated with neurodevelopmental abnormalities and dysmorphic features." Human Genetics 135, no. 7 (April 5, 2016): 699–705. http://dx.doi.org/10.1007/s00439-016-1661-y.
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Chen, Shuo, Yan Wang, Mingyue Xu, Lin Zhang, Yinan Su, Boxue Wang, and Xipeng Zhang. "miR-1184 regulates the proliferation and apoptosis of colon cancer cells via targeting CSNK2A1." Molecular and Cellular Probes 53 (October 2020): 101625. http://dx.doi.org/10.1016/j.mcp.2020.101625.
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Ibrahim, Hussam, Philipp Reus, Anna Katharina Mundorf, Anna-Lena Grothoff, Valerie Rudenko, Christina Buschhaus, Anja Stefanski, et al. "Phosphorylation of GAPVD1 Is Regulated by the PER Complex and Linked to GAPVD1 Degradation." International Journal of Molecular Sciences 22, no. 7 (April 6, 2021): 3787. http://dx.doi.org/10.3390/ijms22073787.
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Repressor protein period (PER) complexes play a central role in the molecular oscillator mechanism of the mammalian circadian clock. While the main role of nuclear PER complexes is transcriptional repression, much less is known about the functions of cytoplasmic PER complexes. We found with a biochemical screen for PER2-interacting proteins that the small GTPase regulator GTPase-activating protein and VPS9 domain-containing protein 1 (GAPVD1), which has been identified previously as a component of cytoplasmic PER complexes in mice, is also a bona fide component of human PER complexes. We show that in situ GAPVD1 is closely associated with casein kinase 1 delta (CSNK1D), a kinase that regulates PER2 levels through a phosphoswitch mechanism, and that CSNK1D regulates the phosphorylation of GAPVD1. Moreover, phosphorylation determines the kinetics of GAPVD1 degradation and is controlled by PER2 and a C-terminal autoinhibitory domain in CSNK1D, indicating that the regulation of GAPVD1 phosphorylation is a novel function of cytoplasmic PER complexes and might be part of the oscillator mechanism or an output function of the circadian clock.
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Wang, Yong-Fei, Yan Zhang, Zhengwei Zhu, Ting-You Wang, David L. Morris, Jiangshan Jane Shen, Huoru Zhang, et al. "Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning." Annals of the Rheumatic Diseases 77, no. 7 (April 6, 2018): 1078–84. http://dx.doi.org/10.1136/annrheumdis-2018-213093.
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ObjectivesSystemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning.MethodsWe conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine-mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning.ResultsWe identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E-08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E-08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE.ConclusionThis study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning.
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Xiao, Jianwei, Rongsheng Wang, Weijian Zhou, Xu Cai, and Zhizhong Ye. "Circular RNA CSNK1G1 promotes the progression of osteoarthritis by targeting the miR‑4428/FUT2 axis." International Journal of Molecular Medicine 47, no. 1 (October 27, 2020): 232–42. http://dx.doi.org/10.3892/ijmm.2020.4772.
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Wirkner, Ute, Hartmut Voss, Wilhelm Ansorge, and Walter Pyerin. "Genomic Organization and Promoter Identification of the Human Protein Kinase CK2 Catalytic Subunit α (CSNK2A1)." Genomics 48, no. 1 (February 1998): 71–78. http://dx.doi.org/10.1006/geno.1997.5136.
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Yang-Feng, Teresa L., Tova Naiman, Idit Kopatz, Dalia Eli, Naomi Dafni, and Dan Canaani. "Assignment of the Human Casein Kinase II α′ Subunit Gene (CSNK2A1) to Chromosome 16p13.2-p13.3." Genomics 19, no. 1 (January 1994): 173. http://dx.doi.org/10.1006/geno.1994.1032.
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Correa, Juan Gonzalo, Alberto Alvarez-Larrán, Monica Lopez-Guerra, Juan Carlos Hernandez Boluda, Mar Tormo, María Rozman, Daniel Martínez, Dolors Colomer, Jordi Esteve, and Francisco Cervantes. "Triple Negative Myelofibrosis and Myelodysplastic Syndrome with Fibrosis: Clinico-Biological Characterization and Correlation with Gene Mutations." Blood 132, Supplement 1 (November 29, 2018): 4299. http://dx.doi.org/10.1182/blood-2018-99-115888.
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Abstract Introduction: Triple negative primary myelofibrosis (TN-PMF) and myelodysplastic syndromes with fibrosis (F-MDS) are rare entities, often difficult to distinguish each other. Currently, no specific molecular markers allowing a precise differential diagnosis are available. In this sense, next generation techniques (NGS) might be useful to distinguish between both entities and to refine prognosis. Methods: Thirty-nine patients with TN-PMF (n=16) or F-MDS (n=23) were analyzed, Targeted NGS was performed in 28 cases (10 TN-PMF and 18 F-MDS) using the Sophia Genetics Myeloid Tumor Solution Panel including the following genes: ABL1, ASXL1, BRAF, CALR, CBL,CEBPA, CSF3R,CSNK1A1,DNMT3A, ETV6, EZH2, FLT3,HRAS, IDH1, IDH2, JAK2, KIT, KMT2A, KRAS, MPL, NPM1, NRAS, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, U2AF2, WT1 and ZRSR2. High molecular risk (HMR) was defined by the presence of any mutation in ASXL1, SRSF2, EZH2 or IDH1/2 genes. Clinical and biological data at diagnosis were compared among both groups of patients, including bone marrow cytogenetics, bone marrow histology, and the results from NGS analysis. The probabilities of survival and progression to acute leukemia were estimated by the Kaplan Meier method using the log rank test for comparisons. Results: Median age at diagnosis for the whole series was 63 years (range 42-87). Cytogenetic abnormalities were detected in 16 (57%) out of 28 assessable patients, being classified as low risk (n=17), intermediate risk (n=5), and high risk (n=6) There were no significant differences among TN-PMF and F-MDS regarding age, sex, hematological values, spleen size or cytogenetic risk or the number of blasts in peripheral blood or bone marrow. Mutations were detected by NGS in 26 out of 28 (93%) patients. Median number of mutations was 3 (Range: 1-7). Most frequent mutated genes were: ASXL1 n=10 (36%), TET2 n=7 (25%), SRSF2 n=6 (21%), DNMT3A n=6 (21%), U2AF1 n=5 (18%), ETV6 n=4 (14%), SETBP1 n=3 (11%), RUNX1 n=3 (11%), EZH2 n=2 (7%), TP53 n=2 (7%), ZRSR2 n=2 (7%) and KMT2A n=2 (7%). Mutations in either TET2, U2AF1, SETBP1, TP53 or RUNX1 genes were observed in only 1 patient with TN-PMF in contrast with 12 out of 18 (67%) F-MDS cases (p=0.006). HMR mutations were detected in 12 cases (43%) with 7 of them (21%) carrying two or more HMR mutations. There were no significant differences among TN-PMF and F-MDS regarding the total number of mutations per case or in the presence of HMR mutations. Median survival was 1.6 and 3.7 years for patients with TN-PMF and F-MDS, respectively (p=0.4). Leukocyte count > 25x109/L and presence of blasts ≥ 1% in peripheral blood were associated with a significantly lower survival. High risk cytogenetics and ≥ 2 HMR mutations were associated with a tendency towards lower survival. Median survival was 1.6 years in patients with ≥ 3 mutations in comparison with 8.3 years in those with < 3 mutations, respectively (p=0.03). Progression to acute myeloid leukemia was observed in 11 patients, resulting in a probability of 32% at 3 years. There were no significant differences in the probability of progression to acute leukemia among TN-PMF and F-MFDS. Time to acute leukemia was significantly shorter in patients with ≥ 3 mutations (3-year probability 45% versus 16%, p=0.039). Conclusions: TN-PMF and F-MDS showed a high rate of mutations in myeloid genes with TET2, U2AF1, SETBP1, TP53 or RUNX1 being more frequently mutated in F-MDS. Despite survival being short in both entities, NGS allowed the identification of a subgroup of patients with especially poor prognosis characterized by the presence of ≥ 3 mutations. Disclosures Hernandez Boluda: Novartis: Consultancy; Incyte: Consultancy. Cervantes:Hospital Clinic Barcelona: Employment; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees.