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Journal articles on the topic 'INK4b'

Author: Grafiati

Published: 4 June 2021

Last updated: 17 February 2022

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1

Malumbres, Marcos, Ignacio Pérez De Castro, María I. Hernández, María Jiménez, Teresa Corral, and Angel Pellicer. "Cellular Response to Oncogenic Ras Involves Induction of the Cdk4 and Cdk6 Inhibitor p15INK4b." Molecular and Cellular Biology 20, no. 8 (April 15, 2000): 2915–25. http://dx.doi.org/10.1128/mcb.20.8.2915-2925.2000.

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ABSTRACT The cell cycle inhibitor p15 INK4b is frequently inactivated by homozygous deletion together with p16 INK4a and p19 ARF in some types of tumors. Although the tumor suppressor capability of p15 INK4b is still questioned, it has been found to be specifically inactivated by hypermethylation in hematopoietic malignancies in the absence of p16 INK4a alterations. Here we show that, in vitro, p15 INK4b is a strong inhibitor of cellular transformation by Ras. Surprisingly, p15 INK4b is induced in cultured cells by oncogenic Ras to an extent similar to that of p16 INK4a , and their expression is associated with premature G1 arrest and senescence. Ras-dependent induction of these two INK4 genes is mediated mainly by the Raf-Mek-Erk pathway. Studies with activated and dominant negative forms of Ras effectors indicate that the Raf-Mek-Erk pathway is essential for induction of both the p15 INK4b and p16 INK4a promoters, although other Ras effector pathways can collaborate, giving rise to a stronger response. Our results indicate that p15 INK4b , by itself, is able to stop cell transformation by Ras and other oncogenes such as Rgr (a new oncogene member of the Ral-GDS family, whose action is mediated through Ras). In fact, embryonic fibroblasts isolated from p15 INK4b knockout mice are susceptible to transformation by the Ras or Rgr oncogene whereas wild-type embryonic fibroblasts are not. Similarly, p15 INK4b -deficient mouse embryo fibroblasts are more sensitive than wild-type cells to transformation by a combination of the Rgr and E1A oncogenes. The cell cycle inhibitor p15 INK4b is therefore involved, at least in some cell types, in the tumor suppressor activity triggered after inappropriate oncogenic Ras activation in the cell.

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2

Klangby, Ulf, Ismail Okan, Kristinn P. Magnusson, Martin Wendland, Peter Lind, and Klas G. Wiman. "p16/INK4a and p15/INK4b Gene Methylation and Absence of p16/INK4a mRNA and Protein Expression in Burkitt's Lymphoma." Blood 91, no. 5 (March 1, 1998): 1680–87. http://dx.doi.org/10.1182/blood.v91.5.1680.

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Abstract The fact that the p16/INK4a and p15/INK4b genes are frequently inactivated in human malignancies and that p16/INK4a null mice spontaneously develop B-cell lymphomas prompted us to examine the status of both genes in Burkitt's Lymphoma (BL). We found a low frequency of p16/INK4a and p15/INK4b deletions and mutations in BL cell lines and biopsies. However, p16/INK4a exon 1 was methylated in 17 out of 19 BL lines (89.5%) and in 8 out of 19 BL biopsies (42%) analyzed. p15/INK4b Exon 1 was also methylated, although at a lower frequency. p16/INK4a mRNA was readily detected in BL lines carrying unmethylated p16/INK4a, but not in those carrying methylated p16/INK4a. No p16/INK4a protein was detected in any of the BL lines and biopsies examined. In contrast, only one out of seven lymphoblastoid cell lines (LCLs) examined was methylated in p16/INK4a exon 1, and three out of the six LCLs with unmethylated p16/INK4a expressed detectable levels of p16/INK4a protein. Thus, the frequent p16/INK4a methylation in BL lines correlates with downregulation of p16/INK4a expression, suggesting that exon 1 methylation is responsible for silencing the p16/INK4a gene in BL.

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3

Klangby, Ulf, Ismail Okan, Kristinn P. Magnusson, Martin Wendland, Peter Lind, and Klas G. Wiman. "p16/INK4a and p15/INK4b Gene Methylation and Absence of p16/INK4a mRNA and Protein Expression in Burkitt's Lymphoma." Blood 91, no. 5 (March 1, 1998): 1680–87. http://dx.doi.org/10.1182/blood.v91.5.1680.1680_1680_1687.

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The fact that the p16/INK4a and p15/INK4b genes are frequently inactivated in human malignancies and that p16/INK4a null mice spontaneously develop B-cell lymphomas prompted us to examine the status of both genes in Burkitt's Lymphoma (BL). We found a low frequency of p16/INK4a and p15/INK4b deletions and mutations in BL cell lines and biopsies. However, p16/INK4a exon 1 was methylated in 17 out of 19 BL lines (89.5%) and in 8 out of 19 BL biopsies (42%) analyzed. p15/INK4b Exon 1 was also methylated, although at a lower frequency. p16/INK4a mRNA was readily detected in BL lines carrying unmethylated p16/INK4a, but not in those carrying methylated p16/INK4a. No p16/INK4a protein was detected in any of the BL lines and biopsies examined. In contrast, only one out of seven lymphoblastoid cell lines (LCLs) examined was methylated in p16/INK4a exon 1, and three out of the six LCLs with unmethylated p16/INK4a expressed detectable levels of p16/INK4a protein. Thus, the frequent p16/INK4a methylation in BL lines correlates with downregulation of p16/INK4a expression, suggesting that exon 1 methylation is responsible for silencing the p16/INK4a gene in BL.

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4

Saunderson, Emily A., Kevin Rouault-Pierre, John G. Gribben, and Gabriella Ficz. "CRISPR/Cas9-Targeted De Novo DNA Methylation Is Maintained and Impacts the Colony Forming Potential of Human Hematopoietic CD34+ Cells." Blood 134, Supplement_1 (November 13, 2019): 2517. http://dx.doi.org/10.1182/blood-2019-130267.

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Introduction The epigenome is significantly perturbed in hematological malignancies with global DNA hypomethylation and localized hypermethylation of gene promoter CpG islands. Whether specific gene promoter hypermethylation can contribute to the clonal expansion of hematopoietic stem and progenitor cells (HSPCs) in humans by affecting HSPC biology, independently of genetic mutations, has not previously been investigated due to the lack of appropriate tools. We show for the first time that it is possible to target de novo DNA methylation using CRISPR/Cas9 in human CD34+ cells isolated from cord blood (CB). DNA methylation targeted to key cell cycle control gene promoters, INK4b (p15) and ARF (p14), is permanently maintained after dCas9 3A3L degradation and inherited as cells differentiate; inhibiting gene expression and affecting the colony forming potential of CD34+ cells. This demonstrates that specific DNA hypermethylation events can permanently change HSPC biology and impact differentiation, potentially contributing to pre-malignant processes. Methods Human CD34+ HSPCs were isolated from human CB and maintained in liquid culture for 24 hours before nucleofection with mRNA encoding an adapted form of CRISPR/Cas9 which has no nuclease activity (dCas9) and is fused to the catalytic domain of DNA methyltransferase 3A (DNMT3A) and 3L (3A3L). The nucleofection cocktail contained dCas9 3A3L or dCas9 3A3L-mut (lacks methyltransferase activity) and 1 to 3 guide RNAs to target DNA methylation to combinations of the INK4a-ARF-INK4b locus. Cells were then seeded into methylcellulose for a primary colony forming assay (CFU). Colonies were scored after 14 days and cells were either harvested and pooled or individual colonies were picked for single-colony molecular analyses. The DNA was extracted and methylation at the INK4a-ARF-INK4b promoters was quantified using targeted bisulfite sequencing; target gene expression was measured using qPCR. The remaining cells from the primary CFU were re-plated a second (secondary CFU) and third (tertiary CFU) time and colonies were again scored after 14 days. Results and Conclusions Targeting DNA methylation to the INK4a-ARF-INK4b locus or INK4b individually in human CD34+ cells resulted in maintenance of hypermethylation at ARF and/or INK4b gene promoters in individual BFU-E (burst-forming unit-erythroid) and CFU-GM (granulocyte, macrophage) colonies as measured by single-colony targeted bisulfite sequencing after the primary CFU; causing heritable repression of INK4b gene expression in the differentiated cells. Some CpGs were up to 90% methylated, indicating that DNA methylation added at these gene promoters is highly stable as cells differentiate. Hypermethylation of ARF and INK4b was found in some colonies even after the tertiary CFU, demonstrating long-term maintenance of promoter hypermethylation. Unexpectedly, no DNA hypermethylation was detected at INK4a in differentiated cells, but whether this is the case for all subpopulations of HSPCs (i.e. HSCs or lymphoid progenitors) is under investigation. Hypermethylation of INK4b and ARF increased the colony forming potential of CD34+ cells in primary, secondary and tertiary CFUs, compared to the control. Conversely, methylation targeted to INK4b alone did not significantly affect the number of colonies in the first CFU, and decreased the number of colonies in the secondary CFU. This suggests a complex interplay between key cell cycle regulators ARF and INK4b in CD34+ cells and during differentiation which can be disrupted by DNA hypermethylation and gene repression. These findings demonstrate the novel insights we can gain by using CRISPR/Cas9 tools to target DNA methylation and these investigations will reveal how gene promoter hypermethylation can impact HSPC function. Furthermore, studying this locus may uncover an important role for DNA hypermethylation in the development of myeloid malignancies, since INK4b is frequently hypermethylated, but rarely mutated, in myeloid dysplastic/proliferative neoplasms and acute myeloid leukemia. Disclosures Gribben: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Acerta/Astra Zeneca: Consultancy, Honoraria, Research Funding.

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Kia, Sima Kheradmand, Marcin M. Gorski, Stavros Giannakopoulos, and C. Peter Verrijzer. "SWI/SNF Mediates Polycomb Eviction and Epigenetic Reprogramming of the INK4b-ARF-INK4a Locus." Molecular and Cellular Biology 28, no. 10 (March 10, 2008): 3457–64. http://dx.doi.org/10.1128/mcb.02019-07.

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ABSTRACT Stable silencing of the INK4b-ARF-INK4a tumor suppressor locus occurs in a variety of human cancers, including malignant rhabdoid tumors (MRTs). MRTs are extremely aggressive cancers caused by the loss of the hSNF5 subunit of the SWI/SNF chromatin-remodeling complex. We found previously that, in MRT cells, hSNF5 is required for p16 INK4a induction, mitotic checkpoint activation, and cellular senescence. Here, we investigated how the balance between Polycomb group (PcG) silencing and SWI/SNF activation affects epigenetic control of the INK4b-ARF-INK4a locus in MRT cells. hSNF5 reexpression in MRT cells caused SWI/SNF recruitment and activation of p15 INK4b and p16 INK4a , but not of p14 ARF . Gene activation by hSNF5 is strictly dependent on the SWI/SNF motor subunit BRG1. SWI/SNF mediates eviction of the PRC1 and PRC2 PcG silencers and extensive chromatin reprogramming. Concomitant with PcG complex removal, the mixed lineage leukemia 1 (MLL1) protein is recruited and active histone marks supplant repressive ones. Strikingly, loss of PcG complexes is accompanied by DNA methyltransferase DNMT3B dissociation and reduced DNA methylation. Thus, various chromatin states can be modulated by SWI/SNF action. Collectively, these findings emphasize the close interconnectivity and dynamics of diverse chromatin modifications in cancer and gene control.

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6

Rosu-Myles, Michael, and Linda Wolff. "p15Ink4b Maintains Normal Levels of Granulocyte-Macrophage Progenitors In Vivo." Blood 106, no. 11 (November 16, 2005): 2280. http://dx.doi.org/10.1182/blood.v106.11.2280.2280.

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Abstract Maintaining a balance between the proliferation and differentiation of hematopoietic stem and progenitor cells is crucial for normal maintenance of the hematopoietic system. The INK4 family of cyclin-dependent kinase inhibitors traditionally function in regulating cell proliferation by blocking G1/S phase transition during cell cycle. Loss of expression of one INK4 family member, p15INK4B, has been associated with acute myeloid leukemia (AML) and myelodysplasia and mice that lack p15Ink4b are more prone to developing retrovirus-induced AML. These data suggest an important role for p15INK4B in myeloid differentiation. Here we examined the hematopoietic progenitor pool in p15Ink4b deficient (Ink4b−/−) mice to determine its potential role in regulating hematopoietic precursors. In myeloid progenitor colony assays, bone marrow (BM) from Ink4b−/− mice were found to contain a 1.4 fold greater number of progenitors committed to the formation of granulocytes and macrophages (CFU-GM). This in vitro data was supported by flow cytometric analysis which determined that Ink4b−/− BM contained a 3-fold greater proportion of granulocyte-macrophage progenitors (GMP) (11+/−1.2% vs 34+/−9%) concomitant with a 2-fold decrease in common myeloid progenitors (CMP) (56+/−2 % vs 34+/−7 %). GMP isolated from Ink4b−/− BM also demonstrated a 3-fold greater propensity to form CFU-GM. Despite these differences, the proportion of cycling GMP or CMP in Ink4b−/− and wt mice were identical as determined by propidium iodide and Hoecsht dye DNA stains and in vivo BrdU incorporation. However, in response to specific cytokines, Ink4b−/− CMP showed an increased potential for GMP differentiation and a decreased capacity to form megakaryocyte-erythroid progenitors (MEP). Our work demonstrates that p15Ink4b functions in maintaining normal levels of CFU-GM and may regulate CMP differentiation in response to specific factors.

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7

Zhang, H., X. Li, L. Ge, J. Yang, J. Sun, and Q. Niu. "Methylation of CpG island of p14(ARK), p15(INK4b) and p16(INK4a) genes in coke oven workers." Human & Experimental Toxicology 34, no. 2 (May 16, 2014): 191–97. http://dx.doi.org/10.1177/0960327114533576.

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To detect the blood genomic DNA methylation in coke oven workers and find a possible early screening index for occupational lung cancer, 74 coke oven workers as the exposed group and 47 water pump workers as the controls were surveyed, and urine samples and peripheral blood mononuclear cells (PBMCs) were collected. Airborne benzo[a]pyrene (B[a]P) levels in workplace and urinary 1-hydroxypyrene (1-OH-Py) levels were determined by high-performance liquid chromatography. DNA damage of PBMCs and the p14(ARK), p15(INK4b) and p16(INK4a) gene CpG island methylation in the promoter region were detected by comet assay and methylation-specific polymerase chain reaction techniques, respectively. Results show that compared with the controls, concentration of airborne B[a]Ps was elevated in the coke plant, and urinary 1-OH-Py’s level and DNA olive tail moment in comet assay were significantly increased in the coke oven workers, and p14(ARK), p15(INK4b) and p16(INK4a) gene methylation rates were also significantly increased. With the working years and urinary 1-OH-Py’s level, the rates of p14(ARK) and p16(INK4a) gene methylation were significantly increased while that of p15(INK4b) gene methylation displayed no statistical change. We conclude that PBMCs’ p14(ARK) and p16(INK4a) gene methylation may be used for screening and warning lung cancer in coke oven workers.

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8

Tasaka, Taizo, James Berenson, Robert Vescio, Toshiyasu Hirama, Carl W. Miller, Masami Nagai, Jiro Takahara, and H. Phillip Koeffler. "Analysis of the p16 INK4A , p15 INK4B and p18 INK4C genes in multiple myeloma." British Journal of Haematology 96, no. 1 (January 1997): 98–102. http://dx.doi.org/10.1046/j.1365-2141.1997.8552482.x.

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9

Nazarenko, M. S., A. V. Markov, I. N. Lebedev, A. A. Sleptsov, J. A. Koroleva, A. V. Frolov, O. L. Barbarash, L. S. Barbarash, and V. P. Puzirev. "Methylation profile of INK4B-ARF-INK4A locus in atherosclerosis." Russian Journal of Genetics 49, no. 6 (June 2013): 681–84. http://dx.doi.org/10.1134/s1022795413060070.

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10

Markus, Jan, Matthew T. Garin, Naomi Galili, Azra Raza, Michael J. Thirman, Michelle M. LeBeau, Janet D. Rowley, and Linda Wolff. "Methylation-Independent Silencing of the Tumor Suppressor p15INK4B by CBFb-SMMHC in Acute Myeloid Leukemias with inv(16)." Blood 106, no. 11 (November 16, 2005): 1615. http://dx.doi.org/10.1182/blood.v106.11.1615.1615.

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Abstract The tumor suppressor INK4B(p15) gene is silenced by CpG island hypermethylation in a majority of acute myeloid leukemias (AML). This silencing can be reversed by the treatment with hypomethylating agents, and these agents are currently being tested for therapeutic intervention. So far, it was not investigated whether or not the INK4B is hypermethylated in all cytogenetic subtypes of AML. Our experiments, which compare levels of INK4B methylation in AML with inv(16), t(8:21) and t(15;17) reveal a strikingly low level of methylation in all leukemias with inv(16). This contrasts with significant levels of DNA methylation in a high proportion of the AML from the other two groups. Surprisingly, even though there is a lack of INK4B methylation in samples from patients with inv(16), expression of the gene is very low when compared to that of PBL from healthy individuals or HL60 cells. Subsequent experiments uncovered a novel mechanism to explain the low level of INK4B expression in the inv(16) AMLs. Overexpression of the aberrant chromosome 16-associated gene CBFb-MYH11 in U937 cells results in failure to induce INK4B in response to vitamin D3. Furthermore, CBFb-SMMHC, encoded by CBFb-MYH11 directly represses transcription from an INK4B promoter in a reporter assay. Electromobility shift assays in the AML-derived cell line ME-1 and U937 cells expressing the fusion gene demonstrate that the repression is due to a change in the composition of the complexes recognizing the binding sites for the transcription regulator CBF. In conclusion, we have found that methylation is not the only way to induce silencing of the tumor suppressor p15INK4B in AML. In inv(16)-containing AML, loss of gene expression is accomplished by the direct transcriptional repressor activity of CBFβ-SMMHC.

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11

Gilley, Jonathan, and Mike Fried. "One INK4 gene and no ARF at the Fugu equivalent of the human INK4A/ARF/INK4B tumour suppressor locus." Oncogene 20, no. 50 (November 2001): 7447–52. http://dx.doi.org/10.1038/sj.onc.1204933.

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Berg, Tobias, Mahmoud Abdelkarim, Yalin Guo, Manfred Fliegauf, and Michael Lübbert. "AML1/ETO Expresssion in Myeloid Leukemia Cells Is Associated with Enhanced Growth-Inhibitory and P15/INK4b Demethylating Effects of 5-AZA-2′-Deoxycytidine." Blood 104, no. 11 (November 16, 2004): 1165. http://dx.doi.org/10.1182/blood.v104.11.1165.1165.

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Abstract The chromosomal translocation (8;21) results in the expression of the chimeric transcription factor AML1/ETO, the most frequent fusion gene in acute myeloid leukemia. The AML1/ETO fusion protein acts as a transcriptional repressor by mediating epigenetic silencing through recruitment of histone deacetylases. Recently, it was shown that it also mediates gene silencing by associating with DNA methyltransferase (Dnmt). We therefore hypothesized that cells expressing AML1/ETO might be preferentially sensitive to the effects of an inhibitor of Dnmt activity, and might provide a superior model for in vitro demethylation and reactivation of the promoter of the p15/INK4b gene (encoding a negative regulator of the cell cycle) that is frequently methylated and silenced in AML and MDS. The 3 myeloid cell lines Kasumi-1 cells (AML1/ETO-positive), KG-1, and KG-1a (both AML1-ETO-negative) are all bearing a heavily methylated p15/INK4b promoter. They were treated with 50 – 1000 nM 5-aza-2′-deoxycytidine (DAC) for three pulses of 24 hrs each. After 6 days, cell growth and viability were determined and FACS analysis performed after propidium iodide staining. Kasumi-1 showed the highest sensitivity to DAC treatment (growth inhibition at 500 nM DAC: Kasumi-1 74.28 %, KG-1 69.16 %, KG-1a 62.38 %). In addition, DAC treatment (500 nM) led to a stronger increase in the sub-G1 fraction in Kasumi-1 (30.46%) compared to KG-1a (20.84 %). Regional p15/INK4b promoter methylation was assessed quantitatively by bisulfite sequencing of ≤10 individual cloned alleles (containing 21 CpGs residues) for calculation of methylated CpG percentage. The p15/INK4b was highly methylated in all 3 cell lines (methylated CpGs Kasumi-1 95.2 %; KG-1 89.6 %; KG-1a 98.4 % ). In Kasumi-1 cells, treatment with DAC resulted in a striking, dose-dependent regional demethylation of the p15/INK4b promoter (demethylated CpGs at 200 nM of DAC: Kasumi-1 63.8 %, KG-1 48.9 %, KG-1a 9.3 %). No demethylating effect was achieved with equitoxic doses of cytarabine or melphalan. Effective demethylation of the p15/INK4b promoter was associated with p15/INK4b protein induction as determined by Western Blot. Simultaneous treatment with all-trans retinoic acid (ATRA) enhanced the effects of DAC treatment upon growth inhibition, but not upon p15/INK4b induction. U937 cells with ecdysone inducible AML1/ETO expression (Fliegauf et al, Oncogene 2004) were also treated with different doses of DAC. When AML1/ETO was induced, U937 cells showed a higher growth inhibition (U937 + AML1/ETO 38.6 %, U937 - AML1/ETO 18 % at 25 nM) and increase in Sub-G1 (U937 + AML1/ETO 18 %, U937 - AML1/ETO 10.55 % at 100 nM) after treatment with DAC. Our results imply that the growth-inhibitory and proapoptotic effect of DAC on leukemia cells is modulated by AML1/ETO protein (or its target genes). The greater accessibility of the p15/INK4b promoter to the demethylating effect of DAC in AML1/ETO expressing Kasumi-1 cells may also be due to differences in regional chromatin structure. With their differential sensitivity to DAC, the cell lines Kasumi-1 and KG-1a provide a model for the different responses of leukemic blasts to DAC.

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13

Aguilo, Francesca, Ming-Ming Zhou, and Martin J. Walsh. "Long Noncoding RNA, Polycomb, and the Ghosts Haunting INK4b-ARF-INK4a Expression: Figure 1." Cancer Research 71, no. 16 (August 9, 2011): 5365–69. http://dx.doi.org/10.1158/0008-5472.can-10-4379.

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Orlow, I., M. Drobnjak, Z. F. Zhang, J. Lewis, J. M. Woodruff, M. F. Brennan, and C. Cordon-Cardo. "Alterations of INK4A and INK4B Genes in Adult Soft Tissue Sarcomas: Effect on Survival." JNCI Journal of the National Cancer Institute 91, no. 1 (January 6, 1999): 73–79. http://dx.doi.org/10.1093/jnci/91.1.73.

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Wang, Jishi, Dan Ma, Qin Fang, Ping Wang, Rui Gao, and Jia Sun. "Down-Regulation of HO-1 Promoted Apoptosis Induced By Decitabine Via Increasing p15INK4B Promoter Demethylation in myelodysplastic syndrome." Blood 124, no. 21 (December 6, 2014): 5213. http://dx.doi.org/10.1182/blood.v124.21.5213.5213.

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Abstract Background: Decitabine, reverts hypermethylation of p15INK4B gene in vitro, was used to improves cytopenias and blast excess in over 50% of patients with high-risk myelodys plastic syndrome (MDS). In this study, over-expression of Heme Oxygenase-1(HO-1) was found in MDS cells line SKM-1 cells, and it was closely related to resistance to apoptosis induced by decitabine. Objective: we aimed to further investigated what role of HO-1 exactly played in apoptosis induced by low-does of decitabine in MDS. Method: CCK-8 kits was used to determine the proliferation inhibition of SKM-1 cells. Flow cytometry was used for analyzing cell proliferation rate and apoptosis. The methylation status and expression of P15INK4B in mRNA and protein levels were measured by methylation-specifc polymerase chain reaction (PCR [MSP]). Apoptosis relative factors expression were detected by real-time transcription and Western blot. Result: Up-regulation of HO-1 by transfected it into SKM-1 cells via lenti-virus vector promoted proliferation and protected cells against apoptosis. In contrast, down-regulation of HO-1 enhanced decitabine-induced apoptosis but reduced accumulation of S phase in cell cycle. To explore the mechanism, we detected cell cycle relative protein expression after SKM-1 cells were treated by decitabine in each group. As a result, over-expression of p15 INK4B and CDK4 were observed in SKM-1 cells which HO-1 was inhibited. And p15 INK4B and CDK4 expression-dependent apoptosis was related to caspase3 pathway. Even though HO-1 was silenced, but apoptotic rate never increased as caspase3 pathway was blocked. Conclusion: As we known that p15 INK4B is a keypoint to regulate S phase of cell cycle, in our study, more obvious demethylation of p15 INK4B was seen in group of SKM-1 cells in which HO-1 was down-regulated. It’s equally in patients’ mononuclear cells who suffered from MDS. The worse the prognosis of MDS was judged, the more the mRNA level of HO-1 expressed. In conclusion, over-expression of HO-1 indicated resistance to demethylation of p15 INK4B induced by decitabine. Disclosures No relevant conflicts of interest to declare.

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Ishiguro, Atsushi, Takenori Takahata, Masato Saito, Gen Yoshiya, Yoshihiro Tamura, Mutsuo Sasaki, and Akihiro Munakata. "Influence of methylated p15 INK4b and p16 INK4a genes on clinicopathological features in colorectal cancer." Journal of Gastroenterology and Hepatology 21, no. 8 (August 2006): 1334–39. http://dx.doi.org/10.1111/j.1440-1746.2006.04137.x.

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Latgé, G., C. Josse, V. Bours, and G. Jerusalem. "44P Role of DNA methylation and non-coding RNA in INK4b-ARF-INK4a locus expression." Annals of Oncology 31 (September 2020): S257. http://dx.doi.org/10.1016/j.annonc.2020.08.196.

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18

Gil, Jesús, and Gordon Peters. "Regulation of the INK4b–ARF–INK4a tumour suppressor locus: all for one or one for all." Nature Reviews Molecular Cell Biology 7, no. 9 (September 2006): 667–77. http://dx.doi.org/10.1038/nrm1987.

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Kordi-Tamandani, Dor Mohammad, Mohammad Ayub Rigi Ladies, Mohammad Hashemi, Abdul-Karim Moazeni-Roodi, Smriti Krishna, and Adam Torkamanzehi. "Analysis of p15 INK4b and p16 INK4a Gene Methylation in Patients with Oral Squamous Cell Carcinoma." Biochemical Genetics 50, no. 5-6 (January 3, 2012): 448–53. http://dx.doi.org/10.1007/s10528-011-9489-6.

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López, Fernando, Teresa Sampedro, José L. Llorente, Mario Hermsen, and César Álvarez-Marcos. "Alterations of p14 ARF , p15 INK4b , and p16 INK4a Genes in Primary Laryngeal Squamous Cell Carcinoma." Pathology & Oncology Research 23, no. 1 (July 4, 2016): 63–71. http://dx.doi.org/10.1007/s12253-016-0083-4.

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Matsumura, I., J. Ishikawa, K. Nakajima, K. Oritani, Y. Tomiyama, J. Miyagawa, T. Kato, H. Miyazaki, Y. Matsuzawa, and Y. Kanakura. "Thrombopoietin-induced differentiation of a human megakaryoblastic leukemia cell line, CMK, involves transcriptional activation of p21(WAF1/Cip1) by STAT5." Molecular and Cellular Biology 17, no. 5 (May 1997): 2933–43. http://dx.doi.org/10.1128/mcb.17.5.2933.

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Although thrombopoietin (TPO) is known to play a fundamental role in both megakaryopoiesis and thrombopoiesis, the molecular mechanism of TPO-induced megakaryocytic differentiation is not known. In a human megakaryoblastic leukemia cell line, CMK, that showed some degree of megakaryocytic differentiation after culture with TPO, the cyclin-dependent kinase (Cdk) inhibitor p21(WAF1/Cip1), but not p27(Kip1), p16(INK4A), p15(INK4B), or p18(INK4C), was found to be upregulated in an immediately early response to TPO. The expression of p21 was found to be sustained over a period of 5 days by treatment with TPO in large polyploid cells that developed in response to TPO, but not in small undifferentiated cells, indicating a close correlation between the ligand-induced differentiation and p21 induction in CMK cells. To examine potential roles of Cdk inhibitors in megakaryocytic differentiation, CMK cells were transfected with the p21, p27, or p16 gene, together with a marker gene, beta-galactosidase, and were cultured with medium alone for 5 days. The ectopic expression of p21 or p27 but not of p16 led to induction of megakaryocytic differentiation of CMK cells. Overexpression of the N-terminal domain (amino acids [aa] 1 to 75) of p21 was sufficient to induce megakaryocytic differentiation, whereas that of the C-terminal domain (aa 76 to 164) had little or no effect on morphological features. Furthermore, we found that although TPO induced tyrosine phosphorylation of both STAT3 and STAT5 in CMK cells, only STAT5 showed binding activities to potential STAT-binding sites that locate in the promoter region of p21 gene (p21-SIE sites), thereby leading to transactivation of p21. These results suggested that p21 induction, possibly mediated through activated STAT5, could play an important role in TPO-induced megakaryocytic differentiation.

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Bisogna, Maria, Jacqueline E. Calvano, Gay Hui Ho, Irene Orlow, Carlos Cordón-Cardó, Patrick I. Borgen, and Kimberly J. Van Zee. "Molecular analysis of the INK4A and INK4B gene loci in human breast cancer cell lines and primary carcinomas." Cancer Genetics and Cytogenetics 125, no. 2 (March 2001): 131–38. http://dx.doi.org/10.1016/s0165-4608(00)00367-8.

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Kim, Jae-Ryong, Seong-Yong Kim, Bong-Hwan Lee, Sang-Woon Kim, Hong-Jin Kim, and Jung-Hye Kim. "Mutations of CDKN2 (MTS1/p16(INK4A)) and MTS2/p15(INK4B) genes in human stomach, hepatocellular, and cholangio-carcinomas." Experimental & Molecular Medicine 29, no. 3 (September 1997): 151–56. http://dx.doi.org/10.1038/emm.1997.22.

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Othman, Moneeb A. K., Martina Rincic, Joana B. Melo, Isabel M. Carreira, Eyad Alhourani, Friederike Hunstig, Anita Glaser, and Thomas Liehr. "A Novel Cryptic Three-Way Translocation t(2;9;18)(p23.2;p21.3;q21.33) with Deletion of Tumor Suppressor Genes in 9p21.3 and 13q14 in a T-Cell Acute Lymphoblastic Leukemia." Leukemia Research and Treatment 2014 (October 8, 2014): 1–7. http://dx.doi.org/10.1155/2014/357123.

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Acute leukemia often presents with pure chromosomal resolution; thus, aberrations may not be detected by banding cytogenetics. Here, a case of 26-year-old male diagnosed with T-cell acute lymphoblastic leukemia (T-ALL) and a normal karyotype after standard GTG-banding was studied retrospectively in detail by molecular cytogenetic and molecular approaches. Besides fluorescence in situ hybridization (FISH), multiplex ligation-dependent probe amplification (MLPA) and high resolution array-comparative genomic hybridization (aCGH) were applied. Thus, cryptic chromosomal aberrations not observed before were detected: three chromosomes were involved in a cytogenetically balanced occurring translocation t(2;9;18)(p23.2;p21.3;q21.33). Besides a translocation t(10;14)(q24;q11) was identified, an aberration known to be common in T-ALL. Due to the three-way translocation deletion of tumor suppressor genes CDKN2A/INK4A/p16, CDKN2B/INK4B/p15, and MTAP/ARF/p14 in 9p21.3 took place. Additionally RB1 in 13q14 was deleted. This patient, considered to have a normal karyotype after low resolution banding cytogenetics, was treated according to general protocol of anticancer therapy (ALL-BFM 95).

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Hamanoue, Satoshi, Miharu Yabe, Hiromasa Yabe, and Takayuki Yamashita. "Hypermethylation of the p15/INK4B Gene in Fanconi Anemia." Blood 104, no. 11 (November 16, 2004): 4296. http://dx.doi.org/10.1182/blood.v104.11.4296.4296.

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Abstract Fanconi anemia (FA) is an inherited bone marrow failure syndrome with multiple complementation groups, characterized by genomic instability and predisposition to MDS and AML. Recent evidence indicates that multiple FA proteins are involved in DNA repair. Thus, increased genetic damage and secondary dysregulation of cell proliferation, differentiation and apoptosis are thought to play important roles in the development of bone marrow failure and subsequent progression to MDS/AML. However, little is known about molecular abnormalities responsible for these hematological disorders. Numerous studies indicated that epigenetic silencing of p15/INK4B, an inhibitor of cyclin-dependent kinases, plays an important role in the pathogenesis of MDS and AML. In the present study, we examined methylation status of 5′ CpG islands of the p15 gene in bone marrow mononuclear cells of FA patients, using methylation-specific PCR (MSP) and combined bisulfite restriction analysis (COBRA). Bone marrow samples were analyzed in 10 patients and serially studied in 4 of them. Hypermethylation of the p15 promoter region was detected in 5 patients (50%). This group included 3 patients with MDS: FA28-1 with refractory anemia (RA), FA87 with RAEB (RA with excess of blasts), and FA88 with later development of RA and progression to RAEB; whereas myelodysplasia was not observed in 2 patients (FA89, FA90). In two cases (FA88, FA90), p15 hypermethylation became negative during their courses, perhaps because of decreased myeloid cells. On the other hand, none of 5 patients without p15 hypermethylation had MDS. These results suggest that p15 hypermethylation is associated with development of MDS and occurs in the early phase of clonal evolution in the disease. Methylation status of p15 may be a useful prognostic factor of FA. Patient Age at onset (year old) Time from onset (month) Cytopenia MDS Cytogenetic abnormalities p15 methylation MSP b p15 methylation COBRA c a siblings, b MSP: methylation specific PCR, c COBRA: combined bisulfite restriction analysis, d ND: not determined FA28-1a 5 128 severe RA − − + 133 severe RA − + ++ FA87 8 252 severe RAEB + + +++ FA88 5 31 moderate − − + +++ 45 severe RA + − − 58 severe RAEB + + + FA89 5 49 mild − − + + 56 severe − − + + FA90 2 2 mild − − + ++ 31 severe − − − − FA28-2a 5 51 mild − − − NDd FA28-3a 3 12 mild − − − NDd FA47 3 15 mild − − − NDd FA68 5 46 moderate − − − NDd FA91 5 129 mild − − − NDd

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26

HEIDENREICH, AXEL, JAYA P. GADDIPATI, JUDD W. MOUL, and SHIV SRIVASTAVA. "MOLECULAR ANALYSIS OF P16 Ink4 /CDKN2 AND P15 Ink4B /MTS2 GENES IN PRIMARY HUMAN TESTICULAR GERM CELL TUMORS." Journal of Urology 159, no. 5 (May 1998): 1725–30. http://dx.doi.org/10.1097/00005392-199805000-00101.

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Kheradmand Kia, Sima, Parham Solaimani Kartalaei, Elnaz Farahbakhshian, Farzin Pourfarzad, Marieke von Lindern, and C. Peter Verrijzer. "EZH2-dependent chromatin looping controls INK4a and INK4b, but not ARF, during human progenitor cell differentiation and cellular senescence." Epigenetics & Chromatin 2, no. 1 (2009): 16. http://dx.doi.org/10.1186/1756-8935-2-16.

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28

Tanaka, Hisashi, Yutaka Shimada, Masayuki Imamura, Ichio Shibagaki, and Kanji Ishizaki. "Multiple types of aberrations in thep16 (INK4a) and thep15(INK4b) genes in 30 esophageal squamous-cell-carcinoma cell lines." International Journal of Cancer 70, no. 4 (February 7, 1997): 437–42. http://dx.doi.org/10.1002/(sici)1097-0215(19970207)70:4<437::aid-ijc11>3.0.co;2-c.

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29

Zhang, Aihua, Chen Gao, Xue Han, Lifang Wang, Chun Yu, Xiaowen Zeng, Liping Chen, Daochuan Li, and Wen Chen. "Inactivation of p 15 INK4b in chronic arsenic poisoning cases." Toxicology Reports 1 (2014): 692–98. http://dx.doi.org/10.1016/j.toxrep.2014.08.007.

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30

Le Frère-Belda, M. A., D. Cappellen, A. Daher, S. Gil-Diez-de-Medina, F. Besse, C. C. Abbou, J. P. Thiery, E. S. Zafrani, D. K. Chopin, and F. Radvanyi. "p15 INK4b in bladder carcinomas: decreased expression in superficial tumours." British Journal of Cancer 85, no. 10 (November 2001): 1515–21. http://dx.doi.org/10.1054/bjoc.2001.2106.

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31

Schmidt, Martina, Juraj Bies, Tomohiko Tamura, Keiko Ozato, and Linda Wolff. "The interferon regulatory factor ICSBP/IRF-8 in combination with PU.1 up-regulates expression of tumor suppressor p15Ink4b in murine myeloid cells." Blood 103, no. 11 (June 1, 2004): 4142–49. http://dx.doi.org/10.1182/blood-2003-01-0285.

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Abstract CDKN2B (INK4B), which encodes the cyclin-dependent kinase inhibitor p15INK4b, is up-regulated by many cytokines found in hematopoietic environments in vivo. In human acute myeloid leukemias (AMLs), it is inactivated with high frequency. To gain insight into the regulatory pathways leading to the normal activation of p15Ink4b expression, we examined interferon β (IFNβ)–induced transcription. Using reporter gene assays in murine myeloid cells M1, we determined that a 328-bp fragment, located 117 to 443 bp upstream of the translation initiation site, was sufficient to activate transcription. Both the interferon consensus sequence-binding protein/interferon regulatory factor 8 (ICSBP/IRF-8) and PU.1 were able to increase transcription from this region. It was determined that both ICSBP and PU.1 must bind to DNA to form a stable PU.1/ICSBP binding complex. Interestingly, introduction of the ICSBP into ICSBP-null Tot2 cells led to a significant increase in p15Ink4b RNA expression. This regulation of the Ink4b promoter is apparently myeloid specific because both ICSBP and PU.1 are myeloid commitment factors. Importantly, this provides a mechanism to explain in part the tumor suppressor activity of ICSBP, since ICSBP-deficient mice develop a chronic myelogenous leukemia (CML)–like disease and a high percentage of human AML and CML lack ICSBP transcripts.

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32

Latalova, Pavla, Katerina Smesny Trtkova, Lucie Navratilova, Vlastimil Scudla, and Jiri Minarik. "Analysis of CpG Island DNA Methylation of p15INK4b and RIL in Bone Marrow Samples of Patients with Monoclonal Gammopathies." Blood 124, no. 21 (December 6, 2014): 5174. http://dx.doi.org/10.1182/blood.v124.21.5174.5174.

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Abstract Introduction: Adding a methyl group on the cytosine residues of CpG dinucleotides (CpGs) is a basic phenomenon in DNA methylation. This modification belongs to a group of epigenetic changes that are thought to play one of the key roles in tumor development and progression. DNA hypermethylation occurs mainly in CpG islands of the promoter region in tumor-supressor (TS) genes, which leads to gene silencing. On the other hand, global DNA hypomethylation leads to a genomic instability. Many specific genes are epigenetically changed in individual malignant diseases and these genes are intensively studied by the scientific community. According to the recent research in plasma cell neoplasms, the global genic hypomethylation is predominant in contrast to hypermethylation events. Epigenetic changes of TS genes may worsen prognosis, drug response and microenvironment interaction in multiple myeloma patients. Our aim was to assess the methylation level of the RIL and p15INK4b gene. RIL protein acts as suppressor of cell proliferation and it sensitizes tumor cells to apoptosis, on the other hand, the p15 INK4bplays an important role in inhibiting the cell cycle progression in G1 phase. Methods: Our updated study includes 72 bone marrow aspirate-samples from 68 patients with multiple myeloma (MM) or monoclonal gammopathy of undetermined significance (MGUS). 68 samples were acquired at the time of the diagnosis and four patients with MM were assessed also in remission after chemotherapy. Extracted DNA after bisulfite modification was examined by pyrosequencing method (Pyromark Q96, Qiagen, Germany) and the selected gene regions – RIL promotor, p15INK4b promotor and p15 INK4b exon were analysed. Nine CpGs in the RIL promoter, thirteen CpGs in the p15INK4b promoter and sixteen CpGs in the p15INK4bexon were studied. Average methylation level (MtL) was generated and samples were sorted according to the mean MtL (%) into four groups for the RIL gene (less than 10% MtL, 11-19% MtL, 21-50% and more than 50%). We used commercially available unmethylated DNA and methylated DNA control. Statistical analysis was performed using Pyromark Software and Wilcoxon rank sum test. Results: Out of the four groups for the methylation level of the RIL gene promoter, the groups with 11-19% MtL and 21-50% MtL, detected significant and highly significant differences respectively at both p-values - p-value ≤0.05 and p-value ≤0.01. There were only 2 samples with MtL level over 50% in patients with active MM, precluding valid statistical analysis. In both regions of the p15 INK4b gene, i.e. the promoter and the exon, we did not find any significant differences between the methylation levels - mean MtL ranged from 3% to 6% in p15INK4b promotor and from 3% to 12% in p15 INK4b exon. The time-dependend analysis of the DNA methylation level changes in four patients assessed at the time of diagnosis and in remission of the disease after chemotherapy course revealed a significant decrease of CpGs methylation in all MM patients reaching therapeutic response. Conclusions: Updated data on the epigenetic analysis in patients with monoclonal gammopathies confirmed an important role of the RIL gene in the epigenetic network acting in pathogenesis of MM. The presented results suggest possible prognostic value and therapeutic target in patients with MM. In contrast, the p15 INK4b gene known as a frequent focus of epigenetic modifications in many tumors, did not show statistically significant differences in our study. Our results indicate that for DNA methylation analyses of MM or MGUS patients, the RIL gene could be more useful marker than the p15 INK4b gene. Moreover, the decrease of the methylation level in patients undergoing systemic chemotherapy might be associated with treatment response, suggesting its potential prognostic value. The paper was supported by the grant IGA MZ CR NT14393. Disclosures No relevant conflicts of interest to declare.

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Hutter, Grit, Miriam Scheubner, Yvonne Zimmermann, Joerg Kalla, Tiemo Katzenberger, Karin Hübler, Sabine Roth, Wolfgang Hiddemann, German Ott, and Martin Dreyling. "Differential effect of epigenetic alterations and genomic deletions of CDK inhibitors [p16(INK4a),p15(INK4b),p14(ARF)] in mantle cell lymphoma." Genes, Chromosomes and Cancer 45, no. 2 (2005): 203–10. http://dx.doi.org/10.1002/gcc.20277.

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34

Wang, Xuan, Yan-Bin Zhu, Hai-Peng Cui, and Ting-Ting Yu. "Aberrant promoter methylation of p15 INK4b and p16 INK4a genes may contribute to the pathogenesis of multiple myeloma: a meta-analysis." Tumor Biology 35, no. 9 (June 8, 2014): 9035–43. http://dx.doi.org/10.1007/s13277-014-2054-2.

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35

Mullighan, Charles G., Letha A. Phillips, Lesli A. Kiedrowski, Jing Ma, Richard T. Williams, Sheila A. Shurtleff, Charles J. Sherr, and James R. Downing. "Ultra-High Resolution Analysis of Genomic Alterations in High-Risk Acute Lymphoblastic Leukemia." Blood 112, no. 11 (November 16, 2008): 2053. http://dx.doi.org/10.1182/blood.v112.11.2053.2053.

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Abstract Previous genomic analyses identified a high frequency of genetic alterations targeting B-lymphoid development (>40%) and cell cycle/tumor suppression (CDKN2A/B, 35%) in pediatric B-progenitor acute lymphoblastic leukemia (B-ALL). The frequency and nature of copy number alterations (CNAs) differs significantly across ALL subtype with less than one CNA/case in MLL ALL and over 8 lesions/case in BCR-ABL1 and ETV6-RUNX1 ALL; and the near obligate presence of IKZF1 (Ikaros) deletion in BCR-ABL1 ALL, but never in ETV6-RUNX1 ALL. Although important insights have been obtained from these genome-wide CNAs, it is important to realize that the SNP array platforms that have been used are limited by uneven probe spacing and poor coverage of some genes (including IKZF1 and CDKN2A/B). Moreover, additional CNAs are detected as array resolution increases (e.g. 6.5 lesions per BCR-ABL1 case using 315,000 markers, and 8.8 for 615,000 marker data). Thus, the true frequency of CNAs in ALL remains unknown. To address this question, we now report ultra-high resolution CNA analysis using 2.17 million feature oligonucleotide arrays (Roche Nimblegen) of 20 MLL, 20 BCR-ABL1, and 4 miscellaneous karyotype B-ALL cases. All had previously been examined using Affymetrix 500K SNP arrays. We identified a mean of 6.2 deletions (range 0–38) and 1.4 gains (0–13) per case. There were more lesions in BCR-ABL1 than MLL ALL cases (mean 11.2 v 1.15 deletions, P<0.0001; 2.3 v 0.45 amplifications, P=0.01). Notably, more lesions were detected by this 2.17 million feature array in comparison to previous Affymetrix SNP array data in BCRABL1 ALL (13.5 v 8.8 lesions/case, P=0.001) but not MLL ALL (1.6 v 1.3 lesions/case, P=NS). Moreover, the Nimblegen platform robustly identified focal deletions in genes poorly covered by SNP arrays (IKZF1, CDKN2A/B) and detected additional deletions not previously identified (e.g. deletion of HBS1L immediately adjacent to MYB). The most common lesions in ALL were deletions of IKZF1 (80% BCR-ABL1, none in MLL), CDKN2A/B (60% BCR-ABL1, 20% MLL) and CNAs of PAX5 (50% BCR-ABL1, 20% MLL). High array resolution enabled PCR-based mapping and sequencing of the genomic breakpoints of multiple recurring deletions (e.g. ADD3, BTLA, CDKN2A/B, C20orf94, HBS1L, IKZF1 and PAX5), each of which bore hallmarks of aberrant RAG-mediated recombination. Due to the small size of the CDKN2A/B genomic locus (41.5 Kb), previous genomic analyses have been unable to accurately determine the frequency of deletion of each of the three tumor suppressors (INK4A, ARF, and INK4B) encoded by this locus. We performed genomic quantitative PCR (gqPCR) across the locus (CDKN2A exons 1b, 1a and 2; CDKN2B exons 1 and 2), which revealed complete concordance between deletions identified by the Nimblegen array and confirmatory gqPCR. However, gqPCR was required to precisely delineate the extent of deletion in each case. All deletions involved both CDKN2A and CDKN2B loci except one MLL case (CDKN2A only), and the same degree of deletion (mono- or bi-allelic) was usually uniform across the locus for each case. Exceptions included two cases harboring homozygous deletions of INK4B and ARF but hemizygous deletion of INK4A, and a case with deletion of ARF-INK4A but not INK4B. To extend this analysis to epigenetic silencing of CDKN2A/B, we performed quantitative methylation analysis of six CDKN2A and two CDKN2B CpG islands by MALDI-TOF mass spectrometry for all BCR-ABL1 cases and 18 CDKN2A/B non-deleted MLL, ETV6-RUNX, and T-ALL cases. Strikingly, whereas high level CpG methylation of CDKN2B and CDKN2A exons 2 and 3 was observed in half the MLL and T-ALL cases, no high level methylation was observed in BCR-ABL1 ALL. These data demonstrate that identification of all CNAs in BCR-ABL1 ALL is critically dependent on array resolution, whereas MLL -rearranged leukemias harbor very few CNAs. Importantly, the use of high density arrays with even probe distribution improves the ability to robustly identify focal CNAs in genes poorly covered by SNP arrays, and to further characterize the mechanism of deletion by sequencing. Furthermore, even with the highest resolution arrays, complementary quantitative PCR across CDKN2A/B is required to precisely define the extent of deletion of this compact gene cluster. Thus, oligonucleotide array or sequencing-based platforms allowing true tiling across the genome will be required to determine the full complement of CNAs in ALL.

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Konuma, Takaaki, and Atsushi Iwama. "The Histone Demethylase Fbxl10/Jhdm1b/Kdm2b Maintains Self-Renewing Hematopoietic Stem Cells." Blood 116, no. 21 (November 19, 2010): 1608. http://dx.doi.org/10.1182/blood.v116.21.1608.1608.

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Abstract Abstract 1608 Post-translational modification of histones, including methylation, acetylation, phosphorylation, and ubiquitination, are central to the epigenetic regulation of transcription, replication and repair. Among these histone modifications, histone methylation marks play a major role in the regulation of development, differentiation, and cell fate decision. Histone methylation marks are reversible and dynamically regulated by two antagonizing groups of enzymes that add and remove methyl groups to histone proteins. Recent identification of a large number of histone demethylases suggests a central role for these enzymes in regulating histone methylation dynamics. However, their roles in hematopoietic stem cells (HSCs) remain poorly understood. Gene-expression analysis of 26 histone demethylases in various hematopoietic populations from mice demonstrated that Fbxl10 (F-box and leucine-rich repeat protein 10)/Jhdm1b/Kdm2b/Ndy1, which is a histone H3 lysine 4 and lysine 36 demethylase, shows the highest levels of expression in CD34-c-Kit+Sca-1+Lineage- (CD34-KSL) HSCs and CD34+KSL multipotent progenitors, but is markedly down-regulated during differentiation in bone marrow, particularly in TER119+ erythroblasts and Gr-1+ granulocytes. Based on these data, we hypothesized that Fbxl10 plays a role in the maintenance of self-renewal capacity or multipotency of HSCs. To address this question, we examined the effects of forced expression of Fbxl10 in CD34-KSL HSCs. CD34-KSL HSCs were transduced with a GFP control or an Fbxl10 retrovirus and then further incubated in the presence of SCF and TPO. At day 14 of culture, although the cumulative cell numbers of the two groups were comparable, the percentage of KSL cells was higher in the Fbxl10 culture than in the GFP control culture. At day 10 of culture, the Fbxl10 culture contained approximately 2-fold more colony-forming cells (CFCs) than the GFP control culture. In particular, the number of high proliferative potential-CFCs (HPP-CFCs), which are defined as colonies with diameter greater than 1mm, was markedly increased in the Fbxl10 culture. Morphological evaluation of the HPP colonies revealed that the Fbxl10 culture contained approximately 20-fold more colony-forming unit-neutrophil/macrophage/Erythroblast/Megakaryocyte (nmEM) compared with the GFP control, indicating that forced expression of Fbxl10 in CD34-KSL HSCs expands colony-forming cells with multi-lineage differentiation potential during ex vivo culture. Next, we performed competitive repopulation assays using 10-day ex vivo cultured cells corresponding to 30 initial CD34-KSL HSCs. Unexpectedly, the chimerism of donor-derived cells overexpressing Fbxl10 in peripheral blood was similar to that of the GFP controls in both primary and secondary transplantation. However, Fbxl10-expressing cells retained significantly higher repopulating capacity in the tertiary transplantation than the GFP control cells, indicating that forced expression of Fbxl10 in CD34-KSL HSCs prevents exhaustion of the long-term repopulating potential of HSCs following serial transplantation. Target genes of Fbxl10 in HSCs have not been documented. The Ink4a-Arf-Ink4b locus is one of the major targets of Fbxl10 reported in mouse embryonic fibroblasts and this locus was also tightly repressed in KSL cells expressing Fbxl10. Chromatin immunoprecipitation (ChIP) assays confirmed the direct binding of flag-tagged Fbxl10 to the Ink4a-Arf-Ink4b locus in transduced cells. Of interest, Fbxl10 still retained positive effects on HSCs even in an Ink4a-Arf-deficient background, suggestive of additional targets of Fbxl10. Taken together with the evidence that the Fbxl10 complex includes the polycomb-group proteins, Ring1b and Bmi1, our findings indicate that Fbxl10 is a novel epigenetic regulator of HSCs which potentially collaborates with the polycomb-group proteins. Disclosures: No relevant conflicts of interest to declare.

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Kawamata, Norihiko, Carl W. Miller, and H. Phillip Koeffler. "Molecular analysis of a family of cyclin-dependent kinase inhibitor genes (p15/MTS2/INK4b andp18/INK4c) in non-small cell lung cancers." Molecular Carcinogenesis 14, no. 4 (December 1995): 263–68. http://dx.doi.org/10.1002/mc.2940140406.

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38

do Nascimento Borges, Bárbara, Rommel Mario Rodriguez Burbano, and Maria Lúcia Harada. "Analysis of the methylation patterns of the p16 INK4A , p15 INK4B , and APC genes in gastric adenocarcinoma patients from a Brazilian population." Tumor Biology 34, no. 4 (March 17, 2013): 2127–33. http://dx.doi.org/10.1007/s13277-013-0742-y.

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Yasaei, H., E. Gilham, J. C. Pickles, T. P. Roberts, M. O'Donovan, and R. F. Newbold. "Carcinogen-specific mutational and epigenetic alterations in INK4A, INK4B and p53 tumour-suppressor genes drive induced senescence bypass in normal diploid mammalian cells." Oncogene 32, no. 2 (March 12, 2012): 171–79. http://dx.doi.org/10.1038/onc.2012.45.

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40

Camacho, Cristel V., Bipasha Mukherjee, Brian McEllin, Liang-Hao Ding, Burong Hu, Amyn A. Habib, Xian-Jin Xie, et al. "Loss of p15/Ink4b accompanies tumorigenesis triggered by complex DNA double-strand breaks." Carcinogenesis 31, no. 10 (July 26, 2010): 1889–96. http://dx.doi.org/10.1093/carcin/bgq153.

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41

Martinez-Delgado, B., M. Robledo, E. Arranz, A. Osorio, MJ García, G. Echezarreta, C. Rivas, and J. Benitez. "Hypermethylation of p15/ink4b/MTS2 gene is differentially implicated among non-Hodgkin’s lymphomas." Leukemia 12, no. 6 (June 1998): 937–41. http://dx.doi.org/10.1038/sj.leu.2401009.

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Zhang, Hong, Huitu Liu, and Fawu Shi. "Effect ofP15 INK4b/MTS2 on the proliferation of human hepatoma cells SMMC-7721." Chinese Science Bulletin 45, no. 15 (August 2000): 1408–12. http://dx.doi.org/10.1007/bf02886248.

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43

Takeuchi, S., CR Bartram, T. Seriu, CW Miller, A. Tobler, JW Janssen, A. Reiter, WD Ludwig, M. Zimmermann, and J. Schwaller. "Analysis of a family of cyclin-dependent kinase inhibitors: p15/MTS2/INK4B, p16/MTS1/INK4A, and p18 genes in acute lymphoblastic leukemia of childhood." Blood 86, no. 2 (July 15, 1995): 755–60. http://dx.doi.org/10.1182/blood.v86.2.755.bloodjournal862755.

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A newly recognized family of proteins that inhibit cyclin-dependent kinases (CDKs) termed cyclin-dependent kinase inhibitors (CDKI) have an important role in regulation of cell-cycle progression. A subfamily of these CDKIs (p15INK4B/MTS2, p16INK4/MTS1, and p18) have a high degree of structural and functional homology and are candidate tumor- suppressor genes. We evaluated the mutational status of the p15, p16, and p18 genes in 103 childhood acute lymphoblastic leukemia (ALL) samples and correlated these results with both their clinical data and additional results concerning their loss of heterozygosity in the region of the p15/p16 genes. Homozygous deletions of the p16 gene occurred extremely frequently in T-ALLs (17/22; 77%), and it was also frequent in precursor-B ALLs (12/81; 15%). Homozygous deletions of the p15 gene were also very frequent in T-ALLs (9/22; 41%), and it occurred in 5 of 81 (6%) precursor-B ALL samples. No deletions of p18 was found in any of the 103 ALL samples. Also, no point mutations of the p15, p16, and p18 genes were detected. We correlated p15/p16 alterations at diagnosis with their clinical characteristics as compared with 2,927 other patients treated similarly. Those with p15/p16 alterations were older; had higher white blood cell counts, often with T-cell ALL phenotype; and more frequently had a mediastinal mass at presentation; but they had the same nonremission, relapse, and survival rates at 5 years as did those patients whose blast cells did not have a p15/p16 deletion. To better understand the extent of alterations affecting chromosome 9p21 (location of the p15/p16 genes), loss of heterozygosity (LOH) was examined at D9S171, which is about 1 megabase proximal to the p15/p16 genes. LOH was detected in 15 of 37 (41%) informative samples. Interestingly, of the 24 informative samples that had no detectable alteration of the p15/p16 genes, 7 samples (29%) had LOH at D9S171. In summary, we show in a very large study that p15 and p16, but not p18, CDKI genes are very frequently altered in ALL; those with p15/p16 alterations are more frequently older children, have higher white blood cells at presentation, and often have a T-cell ALL phenotype. The LOH analysis suggests that another tumor-suppressor gene important in ALL also is present on chromosome 9p21.

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Malumbres, Marcos, Ignacio Pérez de Castro, Javíer Santos, Raül Pérez-Ollé, José Fernández-Piqueras, and Angel Pellicer. "An AC-repeat adjacent to mouse Cdkn2B allows the detection of specific allelic losses in the p15 INK4b and p16 INK4a tumor suppressor genes." Mammalian Genome 9, no. 3 (March 1998): 183–85. http://dx.doi.org/10.1007/s003359900722.

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Zindy, Frederique, Willem den Besten, Bo Chen, Jerold E. Rehg, Esther Latres, Mariano Barbacid, Jeffrey W. Pollard, Charles J. Sherr, Paula E. Cohen, and Martine F. Roussel. "Control of Spermatogenesis in Mice by the Cyclin D-Dependent Kinase Inhibitors p18Ink4c and p19Ink4d." Molecular and Cellular Biology 21, no. 9 (May 1, 2001): 3244–55. http://dx.doi.org/10.1128/mcb.21.9.3244-3255.2001.

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ABSTRACT Male mice lacking both the Ink4c and Ink4dgenes, which encode two inhibitors of D-type cyclin-dependent kinases (Cdks), are infertile, whereas female fecundity is unaffected. Both p18Ink4c and p19Ink4d are expressed in the seminiferous tubules of postnatal wild-type mice, being largely confined to postmitotic spermatocytes undergoing meiosis. Their combined loss is associated with the delayed exit of spermatogonia from the mitotic cell cycle, leading to the retarded appearance of meiotic cells that do not properly differentiate and instead undergo apoptosis at an increased frequency. As a result, mice lacking bothInk4c and Ink4d produce few mature sperm, and the residual spermatozoa have reduced motility and decreased viability. Whether or not Ink4d is present, animals lackingInk4c develop hyperplasia of interstitial testicular Leydig cells, which produce reduced levels of testosterone. The anterior pituitary of fertile mice lacking Ink4c or infertile mice doubly deficient for Ink4c and Ink4d produces normal levels of luteinizing hormone (LH). Therefore, the failure of Leydig cells to produce testosterone is not secondary to defects in LH production, and reduced testosterone levels do not account for infertility in the doubly deficient strain. By contrast,Ink4d-null or double-null mice produce elevated levels of follicle-stimulating hormone (FSH). Because Ink4d-null mice are fertile, increased FSH production by the anterior pituitary is also unlikely to contribute to the sterility observed inInk4c/Ink4d double-null males. Our data indicate that p18Ink4c and p19Ink4d are essential for male fertility. These two Cdk inhibitors collaborate in regulating spermatogenesis, helping to ensure mitotic exit and the normal meiotic maturation of spermatocytes.

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Ye, Fang, and Ningning Li. "Role of p15(INK4B) Methylation in Patients With Myelodysplastic Syndromes: A Systematic Meta-Analysis." Clinical Lymphoma Myeloma and Leukemia 19, no. 6 (June 2019): e259-e265. http://dx.doi.org/10.1016/j.clml.2019.03.013.

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Heyman, Mats, Teresa Calero Moreno, Yie Liu, Dan Grandér, Omid Rasool, Laura Borgonova‐Brandter, Mats Merup, Stefan Söderhäll, and Stefan Einhorn. "Inverse correlation between loss of heterozygosity of the short arm of chromosome 12 and p15 ink4B /p16 ink4 gene inactivation in childhood acute lymphoblastic leukaemia." British Journal of Haematology 98, no. 1 (July 1997): 147–50. http://dx.doi.org/10.1046/j.1365-2141.1997.1843001.x.

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Thomas, Anu Alice, Biao Feng, and Subrata Chakrabarti. "ANRIL regulates production of extracellular matrix proteins and vasoactive factors in diabetic complications." American Journal of Physiology-Endocrinology and Metabolism 314, no. 3 (March 1, 2018): E191—E200. http://dx.doi.org/10.1152/ajpendo.00268.2017.

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noncoding RNAs (lncRNAs) have gained widespread interest due to their prevailing presence in various diseases. lncRNA ANRIL (a. k. a. CDKN2B-AS1) is located on human chromosome 9 (p21.3) and transcribed in opposite direction to the INK4b-ARF-INK4a gene cluster. It has been identified as a highly susceptible region for diseases such as coronary artery diseases and type 2 diabetes. Here, we explored its regulatory role in diabetic nephropathy (DN) and diabetic cardiomyopathy (DCM) in association with epigenetic modifiers p300 and polycomb repressive complex 2 (PRC2) complex. We used an ANRIL-knockout (ANRILKO) mouse model for this study. The wild-type and ANRILKO animals with or without streptozotocin-induced diabetes were monitored for 2 min. At the end of the time point, urine and tissues were collected. The tissues were measured for fibronectin (FN), type IV collagen (Col1α4), and VEGF mRNA and protein expressions. Renal function was determined by the measurement of 24-h urine volume and albumin/creatinine ratio at euthanasia. Renal and cardiac structures were investigated using periodic acid-Schiff stain and/or immunohistochemical analysis. Elevated expressions of extracellular matrix (ECM) proteins were prevented in ANRILKO diabetic animals. Furthermore, ANRILKO had a protective effect on diabetic mouse kidneys, as evidenced by lowering of urine volume and urine albumin levels in comparison with the wild-type diabetic animals. These alterations regulated by ANRIL may be mediated by p300 and enhancer of zeste 2 (EZH2) of the PRC2 complex. Our study concludes that ANRIL regulates functional and structural alterations in the kidneys and hearts in diabetes through controlling the expressions of ECM proteins and VEGF.

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Pacheco, T. R., S. Na, D. A. Norris, W. Weston, and I. H. Maxwell. "Positive regulation of P15 (INK4B), a tumor suppressor gene, in melanoma cell lines by tetracycline." Journal of Dermatological Science 16 (March 1998): S135. http://dx.doi.org/10.1016/s0923-1811(98)83807-3.

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Berg, Tobias, Yalin Guo, Mahmoud Abdelkarim, Manfred Fliegauf, and Michael Lübbert. "Reversal of p15/INK4b hypermethylation in AML1/ETO-positive and -negative myeloid leukemia cell lines." Leukemia Research 31, no. 4 (April 2007): 497–506. http://dx.doi.org/10.1016/j.leukres.2006.08.008.

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