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Sarrou, Evgenia, Laura Richmond, Ruaidhrí J. Carmody, Brenda Gibson e Karen Keeshan. "CRISPR Gene Editing of Murine Blood Stem and Progenitor Cells Induces MLL-AF9 Chromosomal Translocation and MLL-AF9 Leukaemogenesis". International Journal of Molecular Sciences 21, n.º 12 (15 de junho de 2020): 4266. http://dx.doi.org/10.3390/ijms21124266.
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Chromosomal rearrangements of the mixed lineage leukaemia (MLL, also known as KMT2A) gene on chromosome 11q23 are amongst the most common genetic abnormalities observed in human acute leukaemias. MLL rearrangements (MLLr) are the most common cytogenetic abnormalities in infant and childhood acute myeloid leukaemia (AML) and acute lymphocytic leukaemia (ALL) and do not normally acquire secondary mutations compared to other leukaemias. To model these leukaemias, we have used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL-AF9 (MA9) chromosomal rearrangements in murine hematopoietic stem and progenitor cell lines and primary cells. By utilizing a dual-single guide RNA (sgRNA) approach targeting the breakpoint cluster region of murine Mll and Af9 equivalent to that in human MA9 rearrangements, we show efficient de novo generation of MA9 fusion product at the DNA and RNA levels in the bulk population. The leukaemic features of MA9-induced disease were observed including increased clonogenicity, enrichment of c-Kit-positive leukaemic stem cells and increased MA9 target gene expression. This approach provided a rapid and reliable means of de novo generation of Mll-Af9 genetic rearrangements in murine haematopoietic stem and progenitor cells (HSPCs), using CRISPR/Cas9 technology to produce a cellular model of MA9 leukaemias which faithfully reproduces many features of the human disease in vitro.
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Blair, A., e D. H. Pamphilon. "Leukaemic stem cells". Transfusion Medicine 13, n.º 6 (dezembro de 2003): 363–75. http://dx.doi.org/10.1111/j.1365-3148.2003.00464.x.
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Shlush, L. I., e T. Feldman. "The evolution of leukaemia from pre‐leukaemic and leukaemic stem cells". Journal of Internal Medicine 289, n.º 5 (29 de janeiro de 2021): 636–49. http://dx.doi.org/10.1111/joim.13236.
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Lutz, Christoph, Petter Woll, Anders Castor, Helen Ferry, Christina Jensen, Joanne Green, Helene Dreau et al. "Selective Persistence of Distinct Stem/B Leukaemic Stem Cells In Childhood Acute Lymphoblastic Leukaemia In Clinical Remission." Blood 116, n.º 21 (19 de novembro de 2010): 1585. http://dx.doi.org/10.1182/blood.v116.21.1585.1585.
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Abstract Abstract 1585 Recent studies utilising surrogate leukaemic stem cell (LSC) assays have suggested that LSCs in acute lymphoblastic leukaemias (ALLs) might be neither rare, nor phenotypically or functionally distinct. However, studies of candidate LSCs in surrogate assays might not recapitulate the full leukaemic potential of candidate LSCs in patients, and in particular their responsiveness and resistance to therapeutic targeting. Therefore, we have investigated the identity, molecular and functional properties, and persistence of different subsets of candidate LSCs in childhood ALL, at diagnosis and during the course of clinical and molecular remissions in response to chemotherapy, and their relationship to subsequent relapses. First, we investigated 6 patients diagnosed with “good prognosis” TEL-AML1+ ALL, and at diagnosis we found TEL-AML1+ leukaemic cells within the immature B cell progenitor compartment (proB: 34+38+19+), mature B-cells (34-19+), as well as in a population expressing an aberrant combination of stem cell (34+38-/lo) and B-cell (19+) cell surface markers. These stem/B (34+38-/lo19+) cells were all TEL-AML1+ and not present in age-matched normal bone marrow controls. In contrast, haematopoietic stem cells (HSC: 34+38-19-) were not part of the TEL-AML1+ leukaemic clone in any of the patients. 15 days into chemotherapy, all TEL-AML1+ mature B-cells were eliminated in all patients, and this was followed by a clearance of leukaemic proB cells by day 28 of treatment. In striking contrast, leukaemic stem/B cells were still detectable at day 28, but in all TEL-AML1 patients, at later stages all leukaemic cells including the stem/B cells were undetectable, and at the same time these patients went into complete remission with less than 1 leukaemic cell in 10e4 cells detectable. A similar pattern was observed in a case of “high risk” BCR-ABL+ ALL: BCR-ABL+ proB and B-cells were efficiently eliminated by day 90 of the course of chemotherapy, and up to 180 days into the treatment only 34+38-/lo19+ stem/B cells remained part of the BCR-ABL+ clone. In agreement with the persistence of BCR-ABL+ 34+38-/lo19+ stem/B cells, this patient relapsed 17 months after the initiation of chemotherapy. In order to understand the underlying mechanisms of the observed functional and therapeutic heterogeneity seen in leukaemic subpopulations, we performed comparative gene-expression analysis of diagnostic leukaemic stem/B and proB cells of TEL-AML1+ patients. This analysis revealed a differential gene expression pattern between leukaemic stem/B and proB cells, with positive regulators of cell cycle being the most distinctly up regulated genes in leukaemic proB cells. In agreement with this, cell cycle analysis of 3 diagnostic TEL-AML1+ cases also showed proB cells to be more actively cycling compared to the more quiescent state of the leukaemic stem/B compartment (proB: G0 42%; G1 40%; S,G2,M 18% vs. stem/B: G0 81%; G1 18%; S,G2,M 1%), providing a potential mechanistic basis for the relative therapy resistance of ALL stem/B cells. Taken together the present studies suggest that quiescent 34+38-/lo19+ stem/B cells are selectively resistant to chemotherapy, and most likely the origin of relapses when these occur in childhood ALL. Disclosures: No relevant conflicts of interest to declare.
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Noman, Helal Mohammed Mohammed Ahmed, Yahya Saleh Al-Matary, Subbaiah Chary Nimmagadda, Pradeep Kumar Patnana, Longlong Liu, Lanying Wei, Daria Frank, Georg Lenz e Cyrus Khandanpour. "Leukaemia Cells Induced Metabolic Alterations in AML Associated Mesenchymal Stem Cells Via Notch Signalling". Blood 138, Supplement 1 (5 de novembro de 2021): 4347. http://dx.doi.org/10.1182/blood-2021-144468.
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Abstract Introduction: Acute myeloid leukaemia (AML) is a haematological malignancy with a high relapse rate and poor prognosis. Leukaemia cell proliferation is dependent on its interaction with the bone marrow (BM) microenvironment. AML associated mesenchymal stem cells (AML-MSCs) supported the proliferation of leukaemia cells and contributed to disease progression. Stromal microenvironment promoted a metabolic switch but precise underlying molecular mechanisms are poorly understood. Previous studies have demonstrated transfer of functional mitochondria from AML-MSCs to AML blasts facilitating energy requirements. To further improve our understanding of the crosstalk between leukaemia and AML-MSCs, we sought to determine contribution of AML-MSCs and signalling cascades regulating metabolic processes. Methods: Sorted MSCs from non-leukaemic and MLL-AF9 leukaemic mice were isolated, and gene expression profiling was performed using RNA microarray. Additionally sorted MSCs from long-term cultures were cultured alone or with MLL-AF9 leukaemia cells and analysed by RNA-sequencing. Gene set enrichment analysis (GSEA) was used to identify the hallmark gene sets overrepresented in AML-MSCs. We further cocultured murine wild type BM-MSCs alone or together with murine AML cells (C1498 and MLL-AF9) or the control lineage negative cells (Lin -). Metabolic alterations, oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were analysed by Agilent Seahorse XFe96 analyser. Additionally, glucose consumption, lactate secretion and mitochondrial DNA copy number were measured. Results: Microarray analysis in sorted MSCs from leukaemic and non-leukaemic mice have identified hallmark oxidative phosphorylation (p<0.01, NES=-1.6) and glycolysis (p<0.01, NES=-1.3) gene sets to be negatively enriched in AML-MSCs. Interestingly, both the gene sets were also negatively enriched in sorted AML-MSCs when cocultured with leukaemia but not control cells. To validate these findings, we analysed OCR and EACR in WT-MSCs in an identical setting. The oxidative phosphorylation was significantly decreased in MSCs cocultured with C1498 (p<0.0001) and MLL-AF9 (p<0.005) but not with Lin - cells. Interestingly, glycolysis rate, glucose consumption, lactate secretion were significantly decreased in MSCs cocultured with leukaemia cells. Mitochondrial DNA copy number were significantly decreased in MSCs cocultured with C1498 (p<0.001) or MLL-AF9 (p<0.005) but not with control cells. Recent evidence from the lab has demonstrated an essential role for Notch signalling in the leukaemia and AML-MSCs interaction. To functionally determine the crosstalk of leukaemia-MSC interaction and subsequent Notch signalling, we ectopically expressed the Notch intracellular domain (Notch-ICN1) to mimic Notch activation in a murine stromal cell line, MS-5. Confirming Notch activation, Hes1 mRNA expression (encoding a transcriptional target of Notch signalling) was significantly increased in these cells. Underscoring a role for Notch signalling and activation, Notch-ICN1 overexpression in MS-5 cells demonstrated less oxidative phosphorylation and glycolysis rates as compared to MS-5 cells transduced with empty vector. Conclusion: In line with our microarray and GSEA analysis, our findings confirmed that leukaemia cells indeed induced metabolic alterations decreasing oxidative phosphorylation and glycolysis, and thereby potentially altering AML-MSCs function. At the molecular level, Notch signalling (via upregulated Notch1 and 2 expressions and Notch-ICN) in AML-MSCs contributed to metabolic alterations. Therefore, therapeutically interfering this pathway could target the bidirectional interaction between leukaemia and AML-MSCs improving therapeutic efficacy of AML. Disclosures Khandanpour: GSK: Honoraria; Takeda: Honoraria; Janssen: Honoraria; AstraZeneca: Honoraria, Research Funding; Pfizer: Honoraria; Sanofi: Honoraria, Research Funding; BMS/Celgene: Honoraria.
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Bonnet, Dominique. "Normal and leukaemic stem cells". British Journal of Haematology 130, n.º 4 (agosto de 2005): 469–79. http://dx.doi.org/10.1111/j.1365-2141.2005.05596.x.
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Brown, Geoffrey, Lucía Sánchez e Isidro Sánchez-García. "Are Leukaemic Stem Cells Restricted to a Single Cell Lineage?" International Journal of Molecular Sciences 21, n.º 1 (19 de dezembro de 2019): 45. http://dx.doi.org/10.3390/ijms21010045.
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Cancer-stem-cell theory states that most, if not all, cancers arise from a stem/uncommitted cell. This theory revolutionised our view to reflect that cancer consists of a hierarchy of cells that mimic normal cell development. Elegant studies of twins who both developed acute lymphoblastic leukaemia in childhood revealed that at least two genomic insults are required for cancer to develop. These ‘hits’ do not appear to confer a growth advantage to cancer cells, nor do cancer cells appear to be better equipped to survive than normal cells. Cancer cells created by investigators by introducing specific genomic insults generally belong to one cell lineage. For example, transgenic mice in which the LIM-only 2 (LMO2, associated with human acute T-lymphoblastic leukaemia) and BCR-ABLp210 (associated with human chronic myeloid leukaemia) oncogenes were active solely within the haematopoietic stem-cell compartment developed T-lymphocyte and neutrophil lineage-restricted leukaemia, respectively. This recapitulated the human form of these diseases. This ‘hardwiring’ of lineage affiliation, either throughout leukaemic stem cell development or at a particular stage, is different to the behaviour of normal haematopoietic stem cells. While normal cells directly commit to a developmental pathway, they also remain versatile and can develop into a terminally differentiated cell that is not part of the initial lineage. Many cancer stem cells do not have this versatility, and this is an essential difference between normal and cancer stem cells. In this report, we review findings that support this notion.
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Bonnet, D. "Cancer stem cells: AMLs show the way". Biochemical Society Transactions 33, n.º 6 (26 de outubro de 2005): 1531–33. http://dx.doi.org/10.1042/bst0331531.
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The blood-related cancer leukaemia was the first disease where human CSCs (cancer stem cells), or LSCs (leukaemic stem cells), were isolated. The haematopoietic system is one of the best tissues for investigating CSCs, since the developmental hierarchy of normal blood formation is well defined. Leukaemia can now be viewed as aberrant haematopoietic processes initiated by rare LSCs that have maintained or reacquired the capacity for indefinite proliferation through accumulated mutations and/or epigenetic changes. Yet, despite their critical importance, much remains to be learned about the developmental origin of LSCs and the mechanisms responsible for their emergence in the course of the disease. This report will review our current knowledge on LSC development and finally demonstrate how these discoveries provide a paradigm for identification of CSCs from solid tumours.
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Kuek, Vincent, Anastasia M. Hughes, Rishi S. Kotecha e Laurence C. Cheung. "Therapeutic Targeting of the Leukaemia Microenvironment". International Journal of Molecular Sciences 22, n.º 13 (26 de junho de 2021): 6888. http://dx.doi.org/10.3390/ijms22136888.
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In recent decades, the conduct of uniform prospective clinical trials has led to improved remission rates and survival for patients with acute myeloid leukaemia and acute lymphoblastic leukaemia. However, high-risk patients continue to have inferior outcomes, where chemoresistance and relapse are common due to the survival mechanisms utilised by leukaemic cells. One such mechanism is through hijacking of the bone marrow microenvironment, where healthy haematopoietic machinery is transformed or remodelled into a hiding ground or “sanctuary” where leukaemic cells can escape chemotherapy-induced cytotoxicity. The bone marrow microenvironment, which consists of endosteal and vascular niches, can support leukaemogenesis through intercellular “crosstalk” with niche cells, including mesenchymal stem cells, endothelial cells, osteoblasts, and osteoclasts. Here, we summarise the regulatory mechanisms associated with leukaemia–bone marrow niche interaction and provide a comprehensive review of the key therapeutics that target CXCL12/CXCR4, Notch, Wnt/b-catenin, and hypoxia-related signalling pathways within the leukaemic niches and agents involved in remodelling of niche bone and vasculature. From a therapeutic perspective, targeting these cellular interactions is an exciting novel strategy for enhancing treatment efficacy, and further clinical application has significant potential to improve the outcome of patients with leukaemia.
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Shlush, Liran I., Sasan Zandi, Amanda Mitchell, Weihsu Claire Chen, Joseph M. Brandwein, Vikas Gupta, James A. Kennedy et al. "Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia". Nature 506, n.º 7488 (12 de fevereiro de 2014): 328–33. http://dx.doi.org/10.1038/nature13038.
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Hsu, Andy K. W., Beverley M. Kerr, Richard B. Lock, Derek N. J. Hart e Alison M. Rice. "Assembling the Players for Evaluation of Anti-Leukemic CTL Activity in NOD-SCID Mice." Blood 106, n.º 11 (16 de novembro de 2005): 4586. http://dx.doi.org/10.1182/blood.v106.11.4586.4586.
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Abstract Acute Lymphocytic Leukemia (ALL) patients, who relapse after hematopoietic stem cell transplantation, have a poor prognosis with few therapeutic options. An immunotherapeutic approach that enhances the graft versus leukemia effect post transplant may improve the survival of relapsed patients. We postulate that dendritic cells (DC) derived from cord blood CD34+ stem cells will be ideal for this. Further we propose the use of RNA as a source of antigen to induce T cell responses to poorly immunogenic tumours, such as ALL. We have shown that CD34+ cells can expand and differentiate into DC and are functional antigen presenting cells. In addition, we regularly achieve >90% transfection efficiency with >90% cell viability when CD34+-DC are electroporated with eGFP mRNA. Electroporation of CD34+-DC with flu mRNA results in processing, translation and presentation of epitopes by the DC, which are recognised by flu-specific cytotoxic T lymphocytes (CTL). We have induced anti-leukaemic CTL with leukaemic total RNA from the HLA-A2+ NALM-6 cell line. We have established a NOD-SCID mouse model of primary human ALL to test the efficacy of the anti-leukaemic CTL in vivo. Mice engraft within 4–6 weeks of transplantation. Mice transplanted with ALL3 had 93.9±0.8% (BM) and 84.3±4.7% (spleen) CD45+cells at sacrifice. Mice transplanted with ALL7 had 79.1±5.5% and 89.9±1.2% CD45+ cells in the BM and spleen respectively. Cells from the BM and spleen have been cryopreserved and total RNA extracted for later CTL generation. Experiments aimed at replicating the minimal leukaemia burden post transplant, show that the kinetics of appearance of human cells in the blood and the time of palpable splenic engraftment relates to the cell dose. This suggests that while the leukaemic burden is low, the kinetics of growth are identical and thus, by varying the inocula we model emerging relapse. Thus, we have “assembled the players” and are ready to test the efficacy of anti-leukaemic CTL generated by stimulation with RNA loaded CD34+-DC to control in vivo leukaemic growth.
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Ford, Anthony, Chiara Palmi, Clara Bueno, Deborah Knight, Penny Cardus, Dengli Hong, Giovanni Cazzaniga, Tariq Enver e Mel Greaves. "TEL-AML1 Dysregulates the TGFβ Pathway: A Basis for Pre-Leukaemic Stem Cell Selection." Blood 110, n.º 11 (16 de novembro de 2007): 59. http://dx.doi.org/10.1182/blood.v110.11.59.59.
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Abstract TEL-AML1 fusion is the most frequent, defined genetic abnormality in paediatric cancer and is usually an early or initiating and pre-natal event in childhood acute lymphoblastic leukaemia (ALL). Transformation results in the generation of a persistent pre-leukaemic clone, which converts to frank ALL post-natally (at 1-15years) following the acquisition of secondary genetic alterations. The mechanism by which the transcriptional dysregulation imposed by TEL-AML1 impacts on the pre-leukaemic phenotype and disease natural history is unknown. Using regulated expression of TEL-AML1, we show that, in murine progenitor cells, this protein blocks the TGFβ response pathway including the critical regulator of cell cycle inhibition, p27. This inhibition facilitates the selective expansion of otherwise more slowly expanding TEL-AML1 progenitor cells. The mechanism of action of TEL-AML1 appears to operate downstream of SMAD2/3 phosphorylation (by TGFβ signalling) and involves binding of a transcriptional repressor complex to TGFβ target genes. In transgenic Eμ TEL-AML1 mice, we show that early pro-B cells (but not pre-B cells) are selectively expanded and appear less sensitive to the inhibitory effects of TGFβ than equivalent wild-type cells. Finally, we show that expression of TEL-AML1 in human cord blood progenitor cells leads to the expansion of a candidate pre-leukaemic stem cell population with an early B lineage phenotype (CD34+/CD38-/CD19+) that has a selective growth advantage in the presence of TGFβ.
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Skelding, Kathryn A., Daniel L. Barry, Danielle Z. Theron e Lisa F. Lincz. "Bone Marrow Microenvironment as a Source of New Drug Targets for the Treatment of Acute Myeloid Leukaemia". International Journal of Molecular Sciences 24, n.º 1 (29 de dezembro de 2022): 563. http://dx.doi.org/10.3390/ijms24010563.
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Acute myeloid leukaemia (AML) is a heterogeneous disease with one of the worst survival rates of all cancers. The bone marrow microenvironment is increasingly being recognised as an important mediator of AML chemoresistance and relapse, supporting leukaemia stem cell survival through interactions among stromal, haematopoietic progenitor and leukaemic cells. Traditional therapies targeting leukaemic cells have failed to improve long term survival rates, and as such, the bone marrow niche has become a promising new source of potential therapeutic targets, particularly for relapsed and refractory AML. This review briefly discusses the role of the bone marrow microenvironment in AML development and progression, and as a source of novel therapeutic targets for AML. The main focus of this review is on drugs that modulate/target this bone marrow microenvironment and have been examined in in vivo models or clinically.
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Grey, William, Pedro Casado-Izquierdo, Pedro Cutillas e Dominique Bonnet. "Combination Therapy Targeting CKS1-Dependent Protein Degradation Reduces AML Burden Whilst Protecting Normal Haematopoietic Stem Cellsfrom Cytarabine Toxicity". Blood 134, Supplement_1 (13 de novembro de 2019): 2535. http://dx.doi.org/10.1182/blood-2019-121667.
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Human chromosome translocations at 11q23, disrupting the MLL1 gene, result in poor prognostic mixed lineage leukaemias. Current chemotherapy treatment protocols produce an unsatisfactory outcome. Indeed, the average five-year event free survival rate is 44% in paediatric cases, and adult cases have been estimated as low as 15% for two-year survival rates, indicating there is an unmet critical need for more effective therapies. In recent years, there has been great interest in targeting the epigenetic factors involved in MLL-rearranged (MLL-r) leukaemic transformation and maintenance; however, epigenetic plasticity, the potential role of the remaining MLL1 allele and the elusive leukaemic stem cells present in acute myeloid leukaemia (AML), provide many routes to chemoresistance. There is currently great interest in targeting the cell cycle and key intracellular signalling pathways (e.g. Wnt signalling), independent of specific aberrant lesions in AML (e.g. MLL-fusion proteins, DNMT3a mutants), to combat highly quiescent leukaemic stem cells, which are the most difficult to eradicate. In addition, protection of the resident normal haematopoietic stem cells (HSCs), during aggressive induction chemotherapy protocols, provides another route to reduce the competitive advantage of AML cells in vivo. We previously identified two new genes, involved in the regulation of MLL1, Wnt signalling and the cell cycle: the CDK subunits CKS1 and CKS2 (Grey et al. 2017). Here, we investigated the roles of CKS1 and CKS2 during normal and malignant haematopoiesis in vivo, revealing differences in key signalling pathways involved in haematopoiesis and leukaemogenesis, implicating the CKS1/CKS2 axis as a valid therapeutic target. We demonstrate that primary AML patient samples, engrafted in immune deficient mice, are sensitive to inhibition of CKS1-dependent protein degradation, with reduced tumour burden after treatment and significant improvement in survival times. In addition, patient samples showed CKS1-sensitivity irrespective of inherent resistance to Cytarabine. Current chemotherapy protocols, using Cytarabine and Doxorubicin, can be significantly deleterious to resident normal HSCs in vivo. Transient inhibition of CKS1-dependent protein degradation, in vivo, provides a protective function to human CD34+ HSPCs when treated with Cytarabine/Doxorubicin (5+3 dosing protocol), resulting in reduced apoptosis and increased stem cell potential post-therapy. Importantly, combination treatment of CKS1 inhibition with Cytarabine/Doxorubicin significantly reduces AML tumour burden and improves overall survival, by selectively killing AML cells and preserving normal resident HSCs. Altogether, these results open a promising alternative approach for modulating protein phosphorylation and degradation to selectively target leukaemic cells, with the great advantage to protect normal resident HSCs from cytotoxic effects of induction chemotherapy. Disclosures No relevant conflicts of interest to declare.
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Bird, Lucy. "Leukaemic stem cells go under the radar". Nature Reviews Immunology 19, n.º 9 (22 de julho de 2019): 533. http://dx.doi.org/10.1038/s41577-019-0204-x.
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Cox, Charlotte V., Paraskevi Diamanti, Pamela R. Kearns e Allison Blair. "Effects of Steroid Treatment on Childhood ALL Stem Cells." Blood 110, n.º 11 (16 de novembro de 2007): 3462. http://dx.doi.org/10.1182/blood.v110.11.3462.3462.
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Abstract Several lines of evidence indicate a central role for stem cells in the pathogenesis of human leukaemias and exemplify the need to develop strategies that target this sub-population of cells. It is proposed that these cells may exhibit different chemo-sensitivity and consequently may be resistant to drug regimens designed to kill the bulk leukaemia population. Inherently resistant leukaemia stem cells may contribute to subsequent disease relapse. Clearly, there is a need to assess the relative efficacy of therapeutic agents on the sub-populations of cells in addition to the bulk leukaemia. We have previously demonstrated that the sub-population of childhood acute lymphoblastic leukaemia (ALL) cells, capable of serially engrafting NOD/SCID mice, have a CD34+/CD19− or CD34+/CD7− phenotype in B cell precursor (BCP) ALL and T-ALL, respectively. In this investigation we have compared the efficacy of a current glucocorticoid therapeutic agent on these putative ALL stem cells with their effects on the bulk leukaemia population. The effect of dexamethasone (dex), a key component of the treatment of childhood ALL, on primary ALL cells from 13 paediatric cases was examined. Unsorted ALL cells were co-cultured with and without dex for 48 hours. Subsequently, cell viability and apoptosis were evaluated by flow cytometry using propidium iodide and annexin V staining, with Flow-Count fluorospheres to directly determine absolute cell counts. Primary cells from 11 patients with BCP ALL were sorted for expression of CD34/CD19 and cells from 2 T-ALL cases were sorted for expression of CD34/CD7. The unsorted cells and the sorted sub-fractions were co-cultured with increasing concentrations of dex (0.05 to 500 μM) to compare the relative chemosensitivity of the bulk and putative leukaemia stem cell populations. The unsorted leukaemia populations were completely refractory to dex with no significant difference in the levels of apoptosis observed or the absolute number of viable cells in the treated samples and in the untreated controls. Interestingly, when the sorted populations were assessed, an increase in the absolute numbers of viable CD34+/CD19− (1.2–9.7 fold, P<0.02) and CD34+/CD7− (2.6–5 fold, P<0.04) leukaemia cells were observed even at the highest steroid dose, compared to the respective untreated sub-fractions. The other leukaemic sub-fractions did not show a significant increase in the number of viable cells following dex exposure. These data show that 10 out of 11 drug treated primary leukaemia cells were resistant to dex. The putative CD34+/CD19− BCP ALL cells and CD34+/CD7− T-ALL cells showed a significantly enhanced proliferative potential when exposed to the drug, suggesting that it is these cells that may be responsible for disease relapse.
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Gough, NM, RL Williams, DJ Hilton, S. Pease, TA Willson, J. Stahl, DP Gearing, NA Nicola e D. Metcalf. "LIF: a molecule with divergent actions on myeloid leukaemic cells and embryonic stem cells". Reproduction, Fertility and Development 1, n.º 4 (1989): 281. http://dx.doi.org/10.1071/rd9890281.
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We have previously characterized, purified and cloned a novel murine and human regulator [leukaemia inhibitory factor, LIF] which induces the differentiation of certain murine and human myeloid leukaemic cells. Recently we have shown that there are specific LIF receptors on murine embryonic stem [ES] and embryonal carcinoma [EC] cells and that purified recombinant LIF can substitute for feeder cells and crude sources of differentiation inhibiting activity [DIA] [such as BRL-cell-conditioned medium] in the maintenance of ES cells in a pluripotential state in vitro. Furthermore, ES cells maintained in culture in recombinant LIF for a prolonged period can give rise to germline chimaeric mice. Thus, based on a number of biochemical and biological similarities, it is likely that LIF and DIA are the same molecule. The identification of LIF as a molecule, necessary and sufficient for the maintenance of ES cells in culture, should have a profound impact on the use of these cells for genetic manipulations.
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Rodríguez-Pardo, Viviana M., José A. Aristizabal, Diana Jaimes, Sandra M. Quijano, Iliana de los Reyes, María Victoria Herrera, Julio Solano e Jean Paul Vernot. "Mesenchymal stem cells promote leukaemic cells aberrant phenotype from B-cell acute lymphoblastic leukaemia". Hematology/Oncology and Stem Cell Therapy 6, n.º 3-4 (setembro de 2013): 89–100. http://dx.doi.org/10.1016/j.hemonc.2013.09.002.
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Shlush, Liran I., Sasan Zandi, Amanda Mitchell, Weihsu Claire Chen, Joseph M. Brandwein, Vikas Gupta, James A. Kennedy et al. "Erratum: Corrigendum: Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia". Nature 508, n.º 7496 (abril de 2014): 420. http://dx.doi.org/10.1038/nature13190.
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Jawad, Mays, Ullas Mony, Nigel H. Russell e Monica Pallis. "In Vitro Chemosensitivity of Leukaemic Stem and Progenitor Cells to Gemtuzumab Ozogamicin (Mylotarg) in AML." Blood 110, n.º 11 (16 de novembro de 2007): 650. http://dx.doi.org/10.1182/blood.v110.11.650.650.
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Abstract Preliminary data from 1115 patients entered into the MRC AML 15 trial indicated that the addition of Gemtuzumab Ozogamicin (GO) to induction chemotherapy improved disease free survival (Abstract #13, ASH 2006). We hypothesised that this improved survival may be underpinned by the specific therapeutic targeting of leukaemic stem and progenitor cells (LSPC). The LSPC subset of AML cells contains those cells capable of self-renewal in culture and of recapitulating leukaemia in animal models. Successful chemotherapeutic targeting of this subset is essential for complete eradication of leukaemia. We have devised a flow cytometric assay which allows us to measure the in vitro chemosensitivity of the LSPC (CD34+CD38-CD123+) subset in as few as 100 cells and we have used the assay to screen the effectiveness of GO against LSPC. CD123 expression is a determining cell surface marker for leukaemic versus normal stem cells and we were able to demonstrate a significant difference in CD123 MFI values between CD34+CD38- of leukaemic (n= 16) versus normal CD34+ CD38- cells (n= 5; p=0.03), demonstrating the sensitivity of our flow cytometric assay in detecting this leukaemic subset. Blast cells from 14 AML samples were treated with GO (10ng/ml) for 48 hours in an in vitro culture system that maintains LSPC viability. A significant reduction in the number of LSPC (n=14; median 46% cell kill; p= 0.002) as well as AML bulk cells (n=14; median 16% cell kill; p= 0.005) was achieved. This data demonstrates the chemosensitivity of AML cells to GO, particularly to the LSPC subset (p=0.001). Also, the total percentage of LSPC at the start of the assay was found to be positively correlated with GO chemosensitivity (p<0.0001) at 48 hours in in vitro culture (n=14). We have extended culture time for up to 96 hours and preliminary data suggest a further achievable LSPC kill (median 51% cell kill; n= 8). CD33 expression in bulk and CD34+ CD38- populations was explored in the same AML patients. Although CD33 MFI values were highly variable (n= 16; Median = 34.82 and range= 3.7 – 116.54 in bulk fraction and median = 13.69 and range= 0.47 – 436.73 in CD34+ CD38- fraction), we found a significant correlation in CD33 MFI values between bulk and CD34+ CD38- cells (p< 0.0001). Also, the total percentage of CD34+CD38-CD33+ cells was found to be positively correlated with LSPC GO chemosensitivity (n= 14; p= 0.04) after 48 hours of in vitro culture. The GO chemosensitivity of mononuclear cells from mobilised healthy donors was investigated and these were found to be insensitive to this agent both at the bulk cell level and in the CD34+ CD38- subset (mean % cell kill of 10% and 5%, respectively; n=3) after 48 hour in vitro culture. This data establishes the specific targeting of GO to CD123+ CD34+ CD38- and CD33+CD34+ CD38- LSPC, while sparing normal stem and progenitor cells. In conclusion, with many novel agents and drug combinations available for research, we have developed an assay for screening drug effectiveness against LSPC and have demonstrated that GO targets this subset effectively. Combination drugs with GO now need to be further investigated for the complete eradication of LSPC.
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Sun, Qian, Chi-Chiu So, Sze-Fai Yip, Thomas S. K. Wan, Edmond Shiu Kwan Ma e LiChong Chan. "Functional Alterations of Lin−CD34+CD38+ Progenitors in Chronic Myelomonocytic Leukaemia and on Progression to Acute Leukaemia." Blood 110, n.º 11 (16 de novembro de 2007): 4119. http://dx.doi.org/10.1182/blood.v110.11.4119.4119.
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Abstract Chronic myelomonocytic leukaemia (CMML) is a clonal bone marrow stem cell disorder based on the presence of trilineage involvement, the association of myelodysplastic and myeloproliferative features and its ability to transform into acute myeloid leukaemia. The objectives of our study are to identify the cell population and its functional characteristics involved in evolution from CMML phase to acute myeloid leukaemia. We analysed Lin−CD34+ stem/progenitor population and performed cell proliferation, apoptotic assays, self-renewal ability and differentiation potential studies in purified populations of Lin−CD34+CD38− stem cells and Lin−CD34+CD38+ committed progenitors from peripheral blood of 16 patients with CMML and in six of the 16 after transformation to acute myeloid leukaemia (AML-t). We observed an expansion of the stem cell/progenitor pool (Lin−CD34+ cells) in AML-t comprising mainly of Lin−CD34+CD38+ committed progenitors within Lin−CD34+ cells. The Lin−CD34+CD38+ committed progenitors displayed highly proliferative activity in CMML and in AML-t; and additionally acquired resistance to apotosis and myeloid colony self-renewing ability in AML-t. Impairment of dendritic cell (DC) differentiation was observed with complete block in AML-t. Our findings suggest Lin−CD34+CD38+ committed progenitors instead of Lin−CD34+CD38− stem cells could be the target(s) of secondary genetic lesions underpinning progression from CMML to AML. These results have implications for the further study of the biology of leukaemic transformation and the design of new strategies for the effective treatment of CMML.
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Bomken, Simon, Lars Buechler, Klaus Rehe, Frida Ponthan, Helen Blair, Olaf Heidenreich e Josef Vormoor. "Lentiviral Transduction of Patient Derived Leukaemic Blasts Allowing In Vivo Bioluminescent Monitoring in An NSG Model of Leukaemia Stem Cell Maintenance",. Blood 118, n.º 21 (18 de novembro de 2011): 4000. http://dx.doi.org/10.1182/blood.v118.21.4000.4000.
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Abstract Abstract 4000 Serial transplantation of patient derived acute lymphoblastic leukaemia (ALL) blasts continues to contribute to our understanding of the biology of leukaemia stem cells (LSC). Refinement of techniques, and in particular intrafemoral injection and development of the highly immunocompromised NOD/scid IL2Rγ null (NSG) mouse have demonstrated B precursor ALL propagating cells to be both common and present in diverse immunophenotypes. These studies must now be complemented by interrogation of the biological pathways underpinning leukaemia stem cell behaviour and clonal propagation in ALL. We have developed a lentiviral based approach to such studies, using the transfer vector pSLIEW, encoding both enhanced green fluorescent protein (EGFP) and firefly luciferase (luc). We have recently replaced a bone marrow stromal feeder based transduction protocol with a feeder free protocol, removing the risk of co-transduction of feeder cells. Using the feeder free protocol, we have achieved transduction of primary (n=4) and primograft (n=3) material with between 13.0 and 51.4% eGFP positive cells. Transplantation of transduced cells by intrafemoral injection into NSG mice resulted in engraftment and disease dissemination. This process was monitored using an IVIS Spectrum bioluminescence imaging system. This technique demonstrated progression of disease to the contralateral femur, spleen, CNS and vertebrae. Disease progression was also monitored by serial bone marrow punctures and 5-colour flow cytometry, which demonstrated no immunophenotypic bias amongst the transduced cells. Flow cytometry of harvested bone marrow and spleen showed between 5.5% and 10.2% eGFP positive cells representing only a moderate decrease from 26.3% eGFP positivity at initial transplantation. This confirms the relative resistance of the SFFV promoter to silencing, making this approach suitable for serial transplantation. Harvested bone marrow and splenic cells were re-transplanted at 5.5 × 103 – 1.0 × 104 SLIEW+ cells per mouse (total 1 × 105 cells transplanted). Bioluminescent imaging has shown engraftment and dissemination of leukaemia within five weeks, confirming transduction of the leukaemia stem cell compartment. Further development of the pSLIEW vector to include shRNA sequences now offers the potential for functional studies using patient derived material, transduced with a single lentivector construct and serially engrafted in the NSG assay for leukaemic stem cell maintenance. We believe that this approach will allow us to investigate the genetic programmes underpinning leukaemia stem cell self-renewal. Disclosures: No relevant conflicts of interest to declare.
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Sperr, W. R., A. W. Hauswirth, S. Florian, L. Ohler, K. Geissler e P. Valent. "Human leukaemic stem cells: a novel target of therapy". European Journal of Clinical Investigation 34, s2 (agosto de 2004): 31–40. http://dx.doi.org/10.1111/j.0960-135x.2004.01368.x.
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Khan, Ghazala, Kim Orchard e Barbara-ann Guinn. "Antigenic Targets for the Immunotherapy of Acute Myeloid Leukaemia". Journal of Clinical Medicine 8, n.º 2 (23 de janeiro de 2019): 134. http://dx.doi.org/10.3390/jcm8020134.
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One of the most promising approaches to preventing relapse is the stimulation of the body’s own immune system to kill residual cancer cells after conventional therapy has destroyed the bulk of the tumour. In acute myeloid leukaemia (AML), the high frequency with which patients achieve first remission, and the diffuse nature of the disease throughout the periphery, makes immunotherapy particularly appealing following induction and consolidation therapy, using chemotherapy, and where possible stem cell transplantation. Immunotherapy could be used to remove residual disease, including leukaemic stem cells from the farthest recesses of the body, reducing, if not eliminating, the prospect of relapse. The identification of novel antigens that exist at disease presentation and can act as targets for immunotherapy have also proved useful in helping us to gain a better understand of the biology that belies AML. It appears that there is an additional function of leukaemia associated antigens as biomarkers of disease state and survival. Here, we discuss these findings.
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Gezer, Deniz, Amelie V. Guitart, Milica Vukovic, Chithra Subramani, Karen Dunn, Patrick Pollard, Peter J. Ratcliffe, Tessa L. Holyoake e Kamil Kranc. "HIF-1α Is Not Essential For The Establishment Of MLL-Leukaemic Stem Cells". Blood 122, n.º 21 (15 de novembro de 2013): 3767. http://dx.doi.org/10.1182/blood.v122.21.3767.3767.
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Abstract Haematopoietic stem cells (HSCs) reside in hypoxic niches in the bone marrow (BM) and sustain long-life haematopoiesis. HSCs are largely quiescent, self-renew, undergo apoptosis and generate progenitor cells, which differentiate to multiple blood lineages. The strict regulation of the balance between these fate decisions is essential for haematopoiesis and their dysregulation in HSCs and progenitor cells can result in leukaemic transformation. HSCs and leukemic stem cells (LSCs) are suggested to share the same niche and are in need to adapt to hypoxic conditions. Hypoxia-inducible-factor-1α (HIF-1α) is a key mediator of cellular responses to hypoxia and is important for the maintenance of HSC functions under stressful conditions. Furthermore, in chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) HIF-1α is essential for LSC maintenance and ablation or knockdown of HIF-1α leads to exhaustion of established LSCs. The aim of this study was to investigate the requirement for HIF-1α in the generation of pre-LSCs and the establishment of LSCs. To investigate the role of HIF-1α in the generation of pre-LSCs we retrovirally transduced haematopoietic stem and progenitor cells (HSPCs) from either WT or HIF1-αfl/fl Vav-iCre with MLL-ENL retroviruses. Next we performed serial re-plating assays under normoxic and hypoxic conditions to generate pre-LSCs. Surprisingly, WT and HIF-1α deficient HSPCs generated comparable numbers of colonies in normoxia and hypoxia (Fig. 1a). In addition no significant difference was found in the immunophenotypic profile of colonies (Figure 1b). Furthermore, microscopic examination indicated that colonies of all genotypes were dense consistent with their transformed shape (Fig. 1c). WT and HIF-1α-deficient pre-LSCs cultured under normoxia and hypoxia had similar cloning efficiency, which is known to directly correlate with the numbers of LSCs in vivo (Fig. 2). These results indicate that HIF-1α is dispensable for the generation of pre-LSCs. To test the role of HIF-1α in establishment of LSCs from pre-LSCs we transplanted pre-LSCs into lethally irradiated mice together with support BM and monitored the mice for disease development. No significant difference was found in disease latency (Fig. 3a) or frequency of LSCs in peripheral blood, bone marrow or spleens (Fig. 3b) indicating that pre-LSCs lacking HIF-1α can efficiently generate LSCs that cause aggressive AML. In conclusion, we provide genetic evidence that HIF-1α is dispensable for the generation of pre-LSCs and the establishment of LSCs from pre-LSCs. These surprising findings, together with published results indicating that HIF-1α is essential for maintenance of LSCs, imply that HIF-1α has different roles at different stages of leukaemic transformation. Further studies are required to explain the distinct roles of HIF-1α in different stages of leukaemogenesis. Disclosures: Ratcliffe: RedOx: Founder Other. Holyoake:Novartis: Membership on an entity’s Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Ariad: Membership on an entity’s Board of Directors or advisory committees.
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Al-Mawali, Adhra, Avinash Daniel Pinto e Shoaib Al-Zadjali. "CD34+CD38-CD123+ Cells Are Present in Virtually All Acute Myeloid Leukaemia Blasts: A Promising Single Unique Phenotype for Minimal Residual Disease Detection". Acta Haematologica 138, n.º 3 (2017): 175–81. http://dx.doi.org/10.1159/000480448.
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Background/Aims: In CD34-positive acute myeloid leukaemia (AML), the leukaemia-initiating event likely takes place in the CD34+CD38- cell compartment. CD123 has been shown to be a unique marker of leukaemic stem cells within the CD34+CD38- compartment. The aim of this study was to identify the percentage of CD34+CD38-CD123+ cells in AML blasts, AML CD34+CD38- stem cells, and normal and regenerating bone marrow CD34+CD38- stem cells from non-myeloid malignancies. Methods: Thirty-eight adult de novo AML patients with intention to treat were enrolled after the application of inclusion criteria from February 2012 to February 2017. The percentage of the CD34+CD38-CD123+ phenotype in the blast population at diagnosis was determined using a CD45-gating strategy and CD34+ backgating by flow cytometry. We studied the CD34+CD38-CD123+ fraction in AML blasts at diagnosis, and its utility as a unique phenotype for minimal residual disease (MRD) of AML patients. Results: CD123+ cells were present in 97% of AML blasts in patients at diagnosis (median 90%; range 21-99%). CD123+ cells were also present in 97% of the CD34+CD38- compartment (median 0.8164%, range 0.0262-39.7%). Interestingly, CD123 was not present in normal and regenerating CD34+CD38- bone marrow stem cells (range 0.002- 0.067 and 0.004-0.086, respectively). Conclusion: The CD34+CD38-CD123+ phenotype is present in virtually all AML blasts and it may be used as a unique single phenotype for MRD detection in AML patients.
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Dassé, Emilie, Giacomo Volpe, Walter del Pozzo, Jonathan Frampton e Stephanie Dumon. "Distinct c-Myb Regulation by HoxA9, Meis1 and Pbx1 in Haemopoietic and Leukaemic-Like Stem Cells." Blood 114, n.º 22 (20 de novembro de 2009): 1431. http://dx.doi.org/10.1182/blood.v114.22.1431.1431.
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Abstract Abstract 1431 Poster Board I-454 The transcription factor c-Myb is an essential regulator of haemopoiesis and its expression is deregulated in several types of leukaemia. Although some c-Myb functions have been defined, the mechanisms involved in the control of its expression have yet to be elucidated. Previous studies have suggested that transcription initiation at the c-myb gene is constitutive, and that the level of mRNA is regulated by an elongation-blocking mechanism operating in its first intron. Here, we define and compare mechanisms influencing c-myb expression in haemopoietic stem cells (HSCs) versus leukaemic stem cell (LSC)-like cells. Using a nuclease sensitivity assay we have defined several potential regulatory elements in both HSC and LSC-like model cell lines. These hypersensitive sites are in the proximal promoter and the first intron, the latter correlating with the position of the putative transcription elongation regulatory region. Moreover, the hypersensitive sites are located in regions of sequence conservation and encompass a number of potential binding sites for homeodomain (HD)-containing proteins. In this study, we were able to demonstrate that the HD-containing transcription factors HoxA9 and Meis1, which are highly expressed in HSCs and whose co-expression in mouse bone marrow leads to rapid development of acute myeloid leukaemia (AML), are necessary but not sufficient for c-myb expression. In addition, we show that the pre-B-cell leukaemia transcription factor-1 (Pbx1), known to be a key binding partner of HD-containing factors, is indispensable in the regulation of c-myb expression. Comparing the effects of altered levels of HoxA9, Meis1 and Pbx1 in HSCs versus LSCs suggests that distinct mechanisms involving dimeric or trimeric complexes operate to regulate c-myb expression in these two stem cell types. Disclosures No relevant conflicts of interest to declare.
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Gruszka, Alicja M., Debora Valli e Myriam Alcalay. "Wnt Signalling in Acute Myeloid Leukaemia". Cells 8, n.º 11 (7 de novembro de 2019): 1403. http://dx.doi.org/10.3390/cells8111403.
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Acute myeloid leukaemia (AML) is a group of malignant diseases of the haematopoietic system. AML occurs as the result of mutations in haematopoietic stem/progenitor cells, which upregulate Wnt signalling through a variety of mechanisms. Other mechanisms of Wnt activation in AML have been described such as Wnt antagonist inactivation through promoter methylation. Wnt signalling is necessary for the maintenance of leukaemic stem cells. Several molecules involved in or modulating Wnt signalling have a prognostic value in AML. These include: β-catenin, LEF-1, phosphorylated-GSK3β, PSMD2, PPARD, XPNPEP, sFRP2, RUNX1, AXIN2, PCDH17, CXXC5, LLGL1 and PTK7. Targeting Wnt signalling for tumour eradication is an approach that is being explored in haematological and solid tumours. A number of preclinical studies confirms its feasibility, albeit, so far no reliable clinical trial data are available to prove its utility and efficacy.
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Bencomo‐Alvarez, Alfonso E., Andres J. Rubio, Mayra A. Gonzalez e Anna M. Eiring. "Energy metabolism and drug response in myeloid leukaemic stem cells". British Journal of Haematology 186, n.º 4 (24 de junho de 2019): 524–37. http://dx.doi.org/10.1111/bjh.16074.
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van Spronsen, M., T. Westers, R. Mebius, G. J. Schuurhuis, J. Cloos e A. van de Loosdrecht. "Myelodysplastic Syndromes Dissected: Immunophenotypic Aberrant Stem Cells Predict Leukaemic Progression". Leukemia Research 55 (abril de 2017): S126—S127. http://dx.doi.org/10.1016/s0145-2126(17)30330-2.
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Enver, Tariq. "Molecular regulation of normal and leukaemic human haemataopoeitic stem cells". Cell Research 18, S1 (agosto de 2008): S92. http://dx.doi.org/10.1038/cr.2008.182.
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Knight, Robert J., Tracey A. O’Brien, Robert Lindeman e Alla Dolnikov. "Novel Role of Activated Ras in Leukaemogenesis: Induction of Angiogenesis." Blood 108, n.º 11 (16 de novembro de 2006): 1313. http://dx.doi.org/10.1182/blood.v108.11.1313.1313.
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Abstract Mutations in Ras genes are among the most frequent genetic alterations found in leukaemia. Our previous results have indicated that mutant N-ras (N-rasm) expression in the murine haematopoietic progenitor cells results in the development of myeloproliferative disorders that resemble human leukaemia. Our group has recently established a ‘humanised’ NOD/SCID mouse model of Ras-induced leukaemogenesis. N-rasm was transduced into normal human primitive haematopoietic progenitor cells (HPC) using recombinant GFP-expressing retrovirus to initiate the leukaemogenic transformation. When injected in NOD/SCID mice, N-rasm/GFP-expressing HPCs induce a pre-leukaemic condition characterised by the increased expansion of human N-rasm/GFP-positive cells with concomitant myeloid lineage expansion in the bone marrow of the recipient mice. In long-term culture N-rasm induces expansion of primitive CD34+/CD117+ and CD34+CXCR4+ progenitor cells enriched with NOD/SCID repopulating cells as well as myelomonocytic CD34−/CD14+ cells within the expanse of erythroid and lymphoid lineages. Microarray expression analysis revealed the induction of a number of the angiogenic factors and extracellular matrix proteins including VEGF, SDF-1, IL3, PDGF 1 and 2, metalloproteinases 9, 11, 12 and 14 that promote angiogenesis. The expansion of the primitive endothelial (CD34+VEGFR2+) and lymphatic (CD34+VEGFR3+) progenitor cells was consistently observed in N-rasm-transduced cultures. In addition, myelomonocytic CD34−CD14+ cells expanded by N-rasm also appear to contribute to neo-angiogenesis. N-rasm-induced pro-angiogenic factors also act as mitogenic and survival factors for pre-leukaemia HPCs by inhibiting apoptosis and promoting leukaemia-inititating-cell engraftment into the bone marrow of the recipient mice. N-rasm acts to modulate the interaction of leukaemia-initiating-cells with the bone marrow stroma by the induction of extracellular matrix degradation. We propose that the induction of pro-angiogenic factors by N-rasm acts to promote leukaemogenic transformation of leukaermia-inititating stem cells and needs to be investigated as a new candidate therapeutic target for leukaemia.
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Pearson, Stella, Anthony D. Whetton e Andrew Pierce. "Combination of curaxin and tyrosine kinase inhibitors display enhanced killing of primitive Chronic Myeloid Leukaemia cells". PLOS ONE 17, n.º 3 (31 de março de 2022): e0266298. http://dx.doi.org/10.1371/journal.pone.0266298.
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Despite the big increase in precision medicine targeted therapies developing curative treatments for many cancers is still a major challenge due mainly to the development of drug resistance in cancer stem cells. The cancer stem cells are constantly evolving to survive and targeted drug treatment often increases the selective pressure on these cells from which the disease develops. Chronic myeloid leukaemia is a paradigm of cancer stem cell research. Targeted therapies to the causative oncogene, BCR/ABL, have been developed but drug resistance remains a problem. The introduction of tyrosine kinase inhibitors targeting BCR/ABL were transformative in the management of CML. However, patients are rarely cured as the tyrosine kinase inhibitors fail to eradicate the leukaemic stem cell which often leads to loss of response to therapy as drug resistance develops and progression to more fatal forms of acute leukaemia occurs. New treatment strategies targeting other entities within the leukemic stem cell either alone or in combination with tyrosine kinase are therefore required. Drawing on our previous published work on the development of potential novel targets in CML and other myeloproliferative diseases along with analysis of the facilitates chromatin transcription (FACT) complex in CML we hypothesised that curaxin, a drug that targets the FACT complex and is in clinical trial for the treatment of other cancers, could be of use in the treatment of CML. We therefore assessed the curaxin CBL0137 as a new agent to extinguish CML primitive cells and show its ability to preferentially target CML cells compared to healthy control cells, especially in combination with clinically relevant tyrosine kinase inhibitors.
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Newrzela, Sebastian, Christopher Baum, Zhixiong Li, Martin-Leo Hansmann, Sylvia Hartmann, Marianne Hartmann, Kerstin Cornils, Boris Fehse e Dorothee M. von Laer. "A Comparative Analysis of the Leukaemic Potential of Mature T Cells Versus T Cell Precursors." Blood 108, n.º 11 (16 de novembro de 2006): 3248. http://dx.doi.org/10.1182/blood.v108.11.3248.3248.
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Abstract After the report of two cases of leukaemia caused by insertional mutagenesis of a retroviral vector in children with SCID, it became clear that safety issues of therapeutic gene transfer must be addressed more thoroughly. We analysed whether gene transfer into mature T cells and haematopoietic stem cells bear the same risk of generating T cell leukaemia through activation of specific T cell oncogenes, such as LMO2, TCL1 and ΔTrkA. To address this issue, we used the Rag-1 mouse model, which allows long term analysis of transplanted T cells and haematopoietic stem cells. We were able to transduce mature T cells and haematopoietic stem cells of C57BL/6 (Ly5.1) donor mice with oncoretroviral vectors expressing LMO2, TCL1 and ΔTrkA. Transduction efficacies of up to 70% were achieved for mature T cells and approximately 90% for haematopoietic stem cells. After transplantation into Rag-1-deficient recipients, stem cell transplanted animals developed T cell lymphomas/leukemia for all investigated oncogenes after characteristic incubation times, mostly of a CD8+CD4+ double positive phenotype. T cell lymphomas were characterised by gross thymic mass, splenomegaly and heavily enlarged lymph nodes, although none of the control- vector- transduced mice developed lymphoma/leukaemia. LM PCR analysis revealed mono- or oligoclonality of the tumours. T cell transplanted animals showed no signs of leukaemia development so far. However, after several attempts, one immortalized T cell progenitor clone could be generated after transduction with LMO2. Our results so far indicate that mature T cells are less susceptible to transformation by known T cell proto-oncogenes, but the studies are still ongoing.
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Dawson, Mark A., Rab Prinjha, Antje Dittman, George Giotopoulos, Marcus Bantscheff, Wai-In Chan, Samuel Robson et al. "Inhibition of BET Recruitment to Chromatin As An Effective Treatment for MLL-Fusion Leukaemia". Blood 118, n.º 21 (18 de novembro de 2011): 55. http://dx.doi.org/10.1182/blood.v118.21.55.55.
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Abstract Abstract 55 Recurrent chromosomal translocations involving the mixed lineage leukaemia (MLL) gene initiate aggressive forms of leukaemia, which confer a poor prognosis and are often refractory to conventional therapies. Recent efforts have begun to unravel the molecular pathogenesis of these malignancies. Several groups have demonstrated that MLL-fusions associate with two macromolecular chromatin complexes; the polymerase associated factor (PAFc) complex, which interacts with the N-terminal domain of MLL, a portion of the protein that is retained in all the described fusions, or the super elongation complex (SEC), via interaction with the C-terminal fusion partner. These complexes play an integral role in regulating transcriptional elongation and this function appears to be aberrantly co-opted by the MLL-fusions to initiate and perpetuate transcriptional programmes that culminate in leukaemia. In this study we used a systematic global proteomic survey incorporating quantitative mass spectrometry to demonstrate that MLL-fusions, as part of SEC and PAFc complexes, are associated with the BET family of acetyl lysine recognition chromatin “adaptor” proteins. These data provided the basis for therapeutic intervention in MLL-fusion leukaemia, via the displacement of the BET family of proteins from chromatin. Targeting the BET proteins to alter aberrant transcriptional elongation has recently been demonstrated to be possible using small molecule inhibitors that selectively bind the tandem bromodomain at the amino-terminus of the ubiquitously expressed BET proteins (BRD2/BRD3/BRD4). We developed a novel class of potent small molecule inhibitors to the BET family, which is chemically distinct to previously published BET-inhibitors. We then used this new compound (I-BET151) to demonstrate its profound and selective efficacy against human MLL-fusion leukaemic cell lines in liquid culture as well as clonogenic assays in methylcellulose. We also establish that primary murine progenitors retrovirally transformed with MLL-ENL and MLL-AF9 are equally susceptible to treatment with I-BET151. We show that the main phenotypic consequence of BET inhibition in MLL fusion leukaemia is a dramatic early induction of cell cycle arrest and apoptosis. Global gene-expression profiling, following I-BET151 treatment in two different human MLL-fusion leukaemia cell lines (expressing MLL-AF4 and MLL-AF9), highlights a common differentially expressed gene signature that accounts for this phenotype. Importantly, chromatin immunoprecipitation analyses at direct MLL target genes including BCL2, C-MYC and CDK6, indicate that I-BET151 selectively inhibits the recruitment of BET family members BRD3/BRD4, and SEC and PAFc components. These events result in the inefficient phosphorylation and release of paused POL-II from the TSS of these genes providing mechanistic insight into the mode of action of I-BET151 in MLL-fusion leukaemia. We subsequently established the therapeutic efficacy of I-BET151 in vivo by demonstrating dramatic disease control in murine models of MLL-AF4 and MLL-AF9 leukaemia. Finally, we also demonstrate that I-BET151 accelerates apoptosis in primary leukaemic cells from a large number of patients with various MLL-fusion leukaemias, by affecting a similar transcription programme to that identified in the human leukaemic cell lines. Importantly, we also demonstrate that I-BET151 significantly reduces the clonogenic potential of isolated primary leukaemic stem cells, suggesting that disease eradication may be possible. These data highlight a new paradigm for drug discovery targeting the protein-protein interactions of chromatin-associated proteins. We demonstrate that small molecules that perturb the interaction of BRD3/4 with chromatin have therapeutic potential in MLL fusion leukaemias and moreover, we provide the molecular mechanism to account for this therapeutic efficacy. Finally, our results emphasize an emerging role for targeting aberrant transcriptional elongation in oncogenesis. Disclosures: Prinjha: GSK: Employment. Chung:GSK: Employment. Lugo:GSK: Employment. Beinke:GSK: Employment. Soden:GSK: Employment. Mirguet:GSK: Employment. Jeffrey:GSK: Employment. Lee:GSK: Employment. Kouzarides:GSK: Consultancy.
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Cox, Charlotte V., Roger S. Evely, Nicholas J. Goulden e Allison Blair. "Stem Cells in T-ALL Have a Primitive CD133+/CD34+/CD7- Phenotype." Blood 104, n.º 11 (16 de novembro de 2004): 1885. http://dx.doi.org/10.1182/blood.v104.11.1885.1885.
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Abstract The cell of origin of childhood acute lymphoblastic leukaemia (ALL) has been the subject of conflicting reports in recent years. One model suggests that many haemopoietic cell types are susceptible to transformation and the level of commitment of the target cell influences the characteristics of the resulting blast cell population. A second model suggests that primitive haemopoietic cells are the targets for transformation, with some differentiation occurring subsequent to the transformation event. This model suggests a hierarchy of progenitors may exist in ALL. In support of this latter model, we have demonstrated that leukaemic stem cells in B-ALL have a primitive CD34+/CD10−/CD19− phenotype and T-ALL cells with NOD/SCID engrafting capacity are CD34+/CD4−. In this investigation we have attempted to further purify and characterise leukaemic stem cells from children with T-ALL. Cells from 7 patients were sorted for expression of CD34 and CD7 and the sorted subfractions evaluated for long-term proliferative ability in vitro using a serum free suspension culture assay and in the NOD/SCID mouse model. In this group of patients, the CD34+/CD7+ fraction represented 7±6% of cells at sorting, 6±4% were CD34+/CD7− and the majority were CD34−/CD7+ (60±12%). After 3 weeks in culture, the majority of proliferating cells were derived from the CD34+/CD7− subfraction (53±16%). By week 6, >70% of proliferating cells were derived from the CD34+/CD7− subfraction. Unsorted ALL cells and the sorted subfractions from 4 of these patients, were evaluated for their ability to engraft sublethally irradiated NOD/SCID mice. In each case, engraftment was achieved using 105–106 unsorted cells (25–80% CD45+) and with the CD34+/CD7− subfraction only (4–84% CD45+ with 3x103–8x104 cells). There was no engraftment with the other subfractions despite injecting up to 100 fold more cells. The engrafted cells had the same karyotype as the patient at diagnosis and expressed high levels of CD2, CD4 and CD7 implying they had differentiated in vivo. The self-renewal capacity of the CD34+/CD7− cells was evaluated by secondary transplantation. CD45+ cells from NOD/SCIDs engrafted with CD34+/CD7− cells successfully engrafted secondary recipients with equivalent levels of human cell engraftment, demonstrating these cells were capable of self-renewal. These findings suggest that cells with a more primitive phenotype may be the targets for transformation in T-ALL, rather than committed lymphocytes. To further investigate this hypothesis, we sorted cells from 4 of these patients for expression of CD133 and CD7 and evaluated their proliferative ability as described above. Results to date indicate that the CD133+/CD7− fraction represents only 0.35% of nucleated cells at sorting. However, after 3 weeks in culture, 48±9% of proliferating cells were derived from this subfraction and by week 6, 58±20% of cells were derived from the CD133+/CD7− subfraction. In vivo analyses completed in 2 patients to date have shown that only the CD133+/CD7− subfraction was capable of engrafting NOD/SCID mice (0.5–54% CD45+ using 3x103–105 cells). These results demonstrate that T-ALL cells with long-term proliferative and NOD/SCID repopulating capacity express the primitive haemopoietic cell antigens CD133 and CD34 and lack expression of T-lineage markers. These findings add further support to the concept of a common cell of origin for acute leukaemias.
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Goh, Sal Lee, Jean-Pierre Levesque, Allison R. Petitt, Valarie Barbier e Ingrid G. Winkler. "Therapeutic Blockade of Macrophage Colony Stimulating Factor (CSF-1) Delays AML Progression in Mice In Vivo". Blood 128, n.º 22 (2 de dezembro de 2016): 2835. http://dx.doi.org/10.1182/blood.v128.22.2835.2835.
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Abstract Macrophage colony-stimulating factor (M-CSF or CSF-1) plays a role in regulating innate immune responses promoting macrophage growth and differentiation. We hypothesized CSF-1 may also play a role in growth and progression of Acute Myeloid Leukaemia (AML). The aim of this study is to investigate the role of CSF-1 in survival and chemo-resistance of leukaemia stem and progenitor cells (LSPC). We further hypothesized that blocking CSF-1R signalling in LSPC may dampen leukaemia survival in vitro and delay leukaemia progression in vivo. AML was induced in mice by injecting murine Haematopoietic Stem and Progenitor Cells (HSPC) transduced with either MLL-AF9 or AML1- ETO fusion oncogenes for the development of either monomyelocytic or granulocytic leukaemia respectively. We found CSF-1R, the main receptor for CSF-1, was expressed on these acute myeloid leukaemia cells, thus it is possible that CSF-1 provide supportive microenvironment for leukemic growth. To identify whether CSF-1 in the bone marrow (BM) niche is essential for growth of malignant LSPC, we harvested normal or- leukaemic blasts from BM for in vitro studies using Long-Term Culture-Initiating-Cell (LT-CIC) assays. In these assays AML LSPC or normal HSPC cells were co-cultured with mesenchymal stromal cells (MSC) from either wildtype mice (MSC that produce CSF-1) or MSC from OP/OP mice (unable to produce functional CSF-1). We found normal (wild-type) HSPC were able to proliferate, survive and produce LT-CIC in the absence of niche-provided CSF-1, however AML blasts could not, unless rescued by addition of recombinant CSF-1 (100 ng/mL) in vitro. Together these data suggest CSF-1 signalling may be critical for AML LSPC but not normal HSPC. Next we investigated in mice whether therapeutic CSF-1 blockade could similarly dampen AML survival or progression in vivo. Cohorts of mice were injected with luciferase-expressing monomyelocytic (MLL-AF9) BM leukaemic blasts, then 7 days later administered the small molecule CSF-1 antagonist (GW2580, 160mg/kg daily for 10 days) or vehicle control. Leukaemia progression was tracked by biweekly bioluminescence and testbleeds for appearance of GFP+ leukaemia blasts in blood. We found therapeutic blockade of CSF-1 significantly reduced tumour burden in these mice by both bioluminescence and testbleed analysis. Mice were also monitored for duration of survival. As anticipated by the observed reduction in leukaemia burden, therapeutic CSF-1 blockade also significantly extended the duration of overall mouse survival (P<0.005, n= 8 mice/ group). Together these studies suggest therapeutic CSF-1 blockade may show promise as an adjunct therapy to help reduce tumour burden and improve success of AML leukaemia therapies. Disclosures Winkler: GlycoMimetics: Research Funding.
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Toofan, Parto, David Irvine, Lisa Hopcroft, Mhairi Copland e Helen Wheadon. "The role of the bone morphogenetic proteins in leukaemic stem cell persistence". Biochemical Society Transactions 42, n.º 4 (1 de agosto de 2014): 809–15. http://dx.doi.org/10.1042/bst20140037.
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CML (chronic myeloid leukaemia) is characterized by the presence of the oncogenic tyrosine kinase fusion protein BCR (breakpoint cluster region)–Abl, responsible for driving the disease. Current TKI (tyrosine kinase inhibitor) therapies effectively inhibit BCR–Abl to control CML in the majority of patients, but do not eliminate the LSC (leukaemic stem cell) population, which becomes quiescent following treatment. Patients require long-term treatment to sustain remission; alternative strategies are therefore required, either alone or in combination with TKIs to eliminate the LSCs and provide a cure. The embryonic morphogenetic pathways play a key role in haemopoiesis with recent evidence suggesting LSCs are more dependent on these signals following chemotherapy than normal HSCs (haemopoietic stem cells). Recent evidence in the literature and from our group has revealed that the BMP (bone morphogenetic protein) pathway is differentially expressed in CML patients compared with normal donors. In the present review, we explore the role that BMP signalling plays in oesteoblast differentiation, HSC maintenance and the implication of altered BMP signalling on LSC persistence in the BM (bone marrow) niche. Overall, we highlight the BMP pathway as a potential target for developing LSC-directed therapies in CML in the future.
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Pinho, Sandra, Qiaozhi Wei, Maria Maryanovich, Dachuan Zhang, Juan Carlos Balandrán, Halley Pierce, Fumio Nakahara et al. "VCAM1 confers innate immune tolerance on haematopoietic and leukaemic stem cells". Nature Cell Biology 24, n.º 3 (24 de fevereiro de 2022): 290–98. http://dx.doi.org/10.1038/s41556-022-00849-4.
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Drummond, M. W., S. F. Hoare, A. Monaghan, S. M. Graham, M. J. Alcorn, W. N. Keith e T. L. Holyoake. "Dysregulated expression of the major telomerase components in leukaemic stem cells". Leukemia 19, n.º 3 (20 de janeiro de 2005): 381–89. http://dx.doi.org/10.1038/sj.leu.2403616.
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Hotinski, Anya K., Karen M. Lower e Bryone J. Kuss. "Somatic MDC1 Mutation in Putative Pre-Leukaemic Stem Cell of a Biclonal Case of Chronic Lymphocytic Leukaemia". Blood 132, Supplement 1 (29 de novembro de 2018): 5534. http://dx.doi.org/10.1182/blood-2018-99-115704.
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Abstract Chronic lymphocytic leukaemia (CLL) is an inherently heterogeneous disease in which founding lesions and cell of origin remain a subject of debate. This case of truly biclonal CLL provides evidence of the presence of a pre-leukaemic stem cell, supporting other lines of evidence that pathogenic genetic and epigenetic lesions in CLL arise early in haematopoiesis. An individual with trisomy 12 containing CLL, present at a frequency of 30%, was identified. Two distinct CD5/19-positive CLL clones were separated by flow cytometry, based on bimodal expression of CD49d. Each leukaemic clone was subjected to targeted immunoglobulin heavy chain variable region gene (IGHV) sequencing, whole exome sequencing (WES) and single-nucleotide polymorphism (SNP) microarray. CD5-positive T cells and a non-malignant superficial skin biopsy sample from the same individual were analysed as comparators. The CD49d-positive and CD49d-negative fractions harboured completely different IGHV rearrangements and mutational statuses (V4-34*02, hypermutated, and V3-21*02, unmutated, respectively) indicative of two unique leukaemic clones. Furthermore, trisomy 12, a relatively common aneuploidy in CLL, was present at high frequency (89.9%) in the CD49d-positive fraction but was absent in the CD49-negative and T-cell fractions. A mutation in the known CLL driver SF3B1 (c.1866G>T) was present in the CD49-negative, unmutated clone alone, along with a 17p deleted subclone in around 20% of this fraction. The presence of a 17p deletion is highly clinically relevant in this disease, and it is noteworthy that this subclone was not detected by routine fluorescence in situ hybridisation (FISH) at diagnosis. Two putative driver mutations in KMT2D and BCL11B were detected in the CD49d-positive, trisomy 12 clone alone (c.15256C>T and c.1387G>A respectively). A TET2 mutation (c.3609C>G) was found in all three fractions. The mutation in this epigenetic regulator has previously been described in clonal haematopoiesis of indeterminate potential (CHIP) and was hypothesised to have been acquired in a haematopoietic stem cell predisposing the individual to the development of haematological malignancy. However, the presence of this mutation was confirmed by Sanger sequencing of genomic DNA extracted from the skin sample, and is therefore of germline origin. The role of germline TET2 variants has not been described in lymphoid malignancy. Importantly, eight coding mutations were found common to both leukaemic clones but were absent from T-cells, implicating a common cell of origin prior to IGHV rearrangement but following B-lineage commitment (that is, a putative pre-leukaemic stem cell). One of these mutations was a disruptive 123 base pair deletion (c.4824_4946del) in MDC1 (mediator of DNA damage checkpoint 1) and was present at a variant allele frequency (VAF) of approximately 50% in both CLL clones, suggesting it was a founder mutation prior to subclone divergence. MDC1 is a mediator in the Ataxia Telangiectasia Mutated (ATM)-dependent DNA damage repair pathway and has not been previously implicated in CLL pathogenesis unlike ATM, which is frequently lost in del11q CLL. The proposed evolution of CLL in this case is presented in Figure 1. In summary, this highly unusual case of CLL provides insights into the evolution of CLL and adds another line of evidence to support the proposed early origins of CLL in haematopoiesis. The role that MDC1 may contribute to CLL pathogenesis, in particular its association with ATM dysregulation, remains to be elucidated. Further work to delineate critical pathways based on the discovered mutations is underway, and includes global transciptomic analysis of the purified leukaemic clones by RNAseq. Disclosures No relevant conflicts of interest to declare.
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Mony, Ullas, Mays Jawad, Nigel H. Russell e Monica Pallis. "Defined Bone Marrow Niche Components Mediate the In Vitro Resistance of Acute Myeloid Leukaemic Stem and Progenitor Cells (LSPC) to Cytosine Arabinoside." Blood 108, n.º 11 (16 de novembro de 2006): 2543. http://dx.doi.org/10.1182/blood.v108.11.2543.2543.
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Abstract The majority of Acute Myeloid Leukaemia (AML) patients respond to remission-induction chemotherapy, but many patients will suffer disease relapse following induction therapy due to the presence of minimum residual disease (MRD) cells in the bone marrow. Relapse is underpinned by outgrowth of leukaemic stem and progenitor cells (LSPC). We aimed to establish a methodology to distinguish normal from leukaemic SPC, to optimise maintenance of the LSPC phenotype in 48 hour culture and to quantify viable LSPC following culture with and without drugs. The CD34+ CD38− CD123+ high phenotype was used to distinguish LSPC. CD123 fluorescence intensity was measured using fluorescence standards. Miltenyi CD 133 and CD34 coated beads were compared as enrichment strategies. The concentration of LSPC at the start of 48h culture ranged from 0.2 – 16 × 104/ml (median 3.4 × 104/ml). We compared various culture conditions aimed at maintaining these cells in culture without differentiation (i.e. without loss of phenotype), including serum, immobilized fibronectin, SCF, IL-3, IL-6, GM-CSF and angiopoietin-1. We used two flow cytometric assays in parallel for analysis of LSPC survival: in the first assay, viable bulk cells were enumerated using the dye 7-AAD along with an internal standard for cell counting. In the second assay, cells were labelled with CD34FITC, CD123PE, 7-AAD and CD38APC in order to quantify LSPC as a percentage of viable cells. We found that serum-free culture medium, fibronectin-coated wells and a cocktail of IL-3, IL-6, SCF, and angiopoietin-1 was the most successful at maintaining the concentration of CD34+ CD38− CD123+ cells in culture for 48h (median 0% change), although there was considerable variation between samples. We then examined the effect of these niche conditions on the sensitivity of LSPC to cytosine arabinoside (Ara-C). Our data indicates that the survival of LSPC treated with 500 ng/ml Ara-C was 50 per cent of untreated cell survival in the presence of fibronectin and cytokine support (n=9), but 33% per cent of untreated cells survived without this support. Moreover, under these conditions LSPC were less sensitive to Ara-C (median 50% survival, n=10) than unselected cells (median 26% survival). We have defined a system for assessing the in vitro chemosensitivity of LSPC from AML samples to anti-leukaemic agents and have validated the assay by showing that phenotypically-identified LSPC as well as niche components fibronectin and cytokines mediate in vitro resistance to cytosine arabinoside.
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Kats, Lev M., Madison J. Kelly, Gareth Gregory, Ricky W. Johnstone e Stephin J. Vervoort. "BCOR Regulates Cell Fate Transition, Myeloid Differentiation and Leukaemogenesis". Blood 132, Supplement 1 (29 de novembro de 2018): 3907. http://dx.doi.org/10.1182/blood-2018-99-117893.
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Abstract Stem cell self-renewal and lineage specification are highly dynamic and tightly controlled processes that are essential for normal haematopoiesis and are dysregulated in cancer. The X-linked BCL6 Corepressor (BCOR) gene encodes a protein that is widely expressed across adult human tissues and is a component of a non-canonical Polycomb repressive complex 1 (PRC1). The BCOR gene is recurrently mutated in various malignant and non-malignant blood disorders, and we and others have recently provided experimental evidence that BCOR has cell-context dependent functions in regulating the proliferation, differentiation and survival of haematopoietic cells. To comprehensively examine the role of BCOR in haematopoiesis in vivo we used a conditional mouse model that mimics the truncating mutations observed in acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS). Using stem and progenitor populations isolated ex vivo we comprehensively analysed the role of BCOR in regulating gene expression, modifying chromatin and altering genome architecture. We demonstrate that BCOR has a pivotal role in down-regulating haematopoietic stem cell (HSC) associated transcriptional networks during the transition from multi-potent stem cells to lineage-committed myeloid progenitors. Inactivation of Bcor in HSCs results in expansion of myeloid progenitors and co-operates with oncogenic KrasG12D in the initiation of an aggressive and fully transplantable acute leukaemia. Mechanistically, Bcor regulates a subset of PRC1-target genes including key HSC super-enhancer-linked transcription factors that are normally down-regulated during myeloid differentiation. We used CRISPR/Cas9 to explore the function of Bcor target genes and identified those that are necessary for the proliferation of Bcor mutant leukaemic cells. This study provides a comprehensive mechanistic understanding of how BCOR regulates cell fate decisions and contributes to the development of leukaemia. Disclosures No relevant conflicts of interest to declare.
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Volpe, Giacomo, David Walton, Emilie Dassé, Walter del Pozzo, Laura O'Neill, Berthold Göttgens, Jonathan Frampton e Stephanie Dumon. "Distinct Mechanisms Regulate the Expression of flt3 Gene in Normal and Leukaemia-Like Stem Cells." Blood 114, n.º 22 (20 de novembro de 2009): 4586. http://dx.doi.org/10.1182/blood.v114.22.4586.4586.
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Abstract Abstract 4586 The interaction between the tyrosine kinase receptor Flt3 and its ligand FL leads to crucial signalling during the early stages of the commitment of haematopoietic stem cells (HSCs). Consequent to mutations or over-expression, constitutive activation of the Flt3/FL pathway is also a key factor in the enhanced survival and expansion of leukaemic cells. Flt3 expression is in particular a feature of Acute Myeloid Leukemia (AML) as it is found in the vast majority of cases. As well as a powerful inducer of leukaemogenesis, Flt3 expression could therefore be viewed as a measurable consequence of the leukaemic transcriptional programme. Hence, understanding its transcriptional regulation would improve our knowledge of the molecular events underlying normal stem cell commitment and AML disease. Accounting for 40% of AML cases, normal cytogenetic AML (NC-AML) is a heterogeneous group of diseases that present a number of different alterations in transcriptional regulators of haematopoiesis, including mutations (MLL, C/EBPα, AML1, PU.1, GATA-1) or altered expression brought about by silencing (C/EBPα, PU.1) or activation (MN1, MLL, ERG1, Cdx2, Hox proteins). Here, we show that a substantial number of these transcription factors are implicated in the regulation of the flt3 gene, and by comparing cell line models of normal HSCs and AML, we pinpoint the importance of HoxA9, Meis1, C/EBPα and c-Myb, and remodelling of the epigenetic environment in the regulation of flt3 expression in leukaemic cells. C/EBPa mutations are found in 10% of AML cases and are considered to be associated with a good prognosis in the absence of Flt3 constitutive activation. We present a model linking C/EBPα and c-Myb activity to flt3 gene expression and FLT3 signalling. Disclosures: No relevant conflicts of interest to declare.
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Hokland, Peter, Petter S. Woll, Marcus C. Hansen e Marie Bill. "The concept of leukaemic stem cells in acute myeloid leukaemia 25 years on: hitting a moving target". British Journal of Haematology 187, n.º 2 (2 de agosto de 2019): 144–56. http://dx.doi.org/10.1111/bjh.16104.
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Zenati, Abdelhafid, Messaoud Chakir e Mohamed Tadjine. "Study of cohabitation and interconnection effects on normal and leukaemic stem cells dynamics in acute myeloid leukaemia". IET Systems Biology 12, n.º 6 (dezembro de 2018): 279–88. http://dx.doi.org/10.1049/iet-syb.2018.5026.
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Winkler, Ingrid G., Valerie Barbier, Diwakar R. Pattabiraman, Thomas J. Gonda, John L. Magnani e Jean-Pierre Levesque. "Vascular Niche E-Selectin Protects Acute Myeloid Leukaemia Stem Cells from Chemotherapy". Blood 124, n.º 21 (6 de dezembro de 2014): 620. http://dx.doi.org/10.1182/blood.v124.21.620.620.
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Abstract We recently reported that vascular adhesion molecule E-selectin is a key component of the bone marrow vascular niche, ‘awakening’ otherwise dormant Haematopoietic Stem Cells (HSC) (Winkler et al., Nat Med 2012). Following cytotoxic chemotherapy or radiation injury, E-selectin expression in the bone marrow increases ~10 to 20-fold during the recovery phase, at a time when HSC must cycle to replenish the blood and immune systems. When E-selectin is absent (in gene deleted mice) or E-selectin is therapeutically blocked using the small molecule glycomimetic antagonist GMI-1271, a greater proportion of HSC return to quiescence following radiation or chemotherapy. We now report cell surface E-selectin to be also upregulated 5 to 10-fold on the BM vasculature in mice with acute myeloid leukaemia (AML). This raises the interesting question: how do AML leukaemia stem cells (LSC) respond to E-selectin at the vascular niche? Using models of murine AML generated by retroviral transduction of the MLL-AF9 fusion oncogene into HSC, we found leukemic blasts rapidly upregulate E-selectin binding potential upon oncogenic transformation. In fact targeted disruption of these E-selectin-mediated interactions by administration of GMI-1271 injection distrupts adhesion and localization of AML cells and was sufficient to continually mobilise leukaemic blasts into the blood for at least 24 hours after a single injection at 40 mg/kg, suggesting that E-selectin-mediated interactions play a role in retaining LSC within BM niches. We next queried whether E-selectin-mediated signalling may help promote LSC survival following therapy. To test this, cohorts of 20 wildtype or 20 E-selectin knock-out mice were transplanted with the same AML cells, then 4 weeks later, half were treated with high dose cytarabine (2 x 900mg/kg at 12hour interval) while the other half remained untreated. At 24 hours after the first cytarabine injection, BM cells were harvested to measure numbers of surviving functional LSC by limiting-dilution transplantation assays in irradiated wild-type syngenic recipients and the proportion of these recipients that developed leukemia was used to calculate the original number of surviving LSC by Poisson’s distribution. We found that although the absence of E-selectin had no effect on total LSC numbers per femur, the absence of E-selectin dramatically increased sensitivity of LSC to cytarabine treatment (20-fold). These results indeed suggest that E-selectin is a key vascular niche component mediating LSC chemoresistance. Our data are also consistent with previous xenograft models in immune-deficient mice showing that the few human CD34+ AML LSC that survived chemotherapy, were observed clustered around endosteal vascular endothelium in recipient mice (Ishikawa et al., Nat BioTechnol 2007; Ninomiya et al., Leukemia 2007) where E-selectin is expressed. In summary our data confirm that niche factors alone can strongly influence LSC sensitivity to chemotherapy, and suggest a chemoprotective role for the vascular adhesion molecule E-selectin which is upregulated in the bone marrow of leukaemic mice, Taken together, these data identify E-selectin as a novel therapeutic target for the treatment of AML leukemic stem cells in that in vivo inhibition by the small molecule glycomimetic E-selectin antagonist GMI-1271 may improve chemosensitivity. Disclosures Winkler: FibroGen Inc.: Research Funding. Magnani:GlycoMimetics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
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Karki, Nabin Raj, Kristine Badin, Natasha Savage e Locke Bryan. "Leukaemic relapse of anaplastic large cell lymphoma, ALK negative". BMJ Case Reports 14, n.º 2 (fevereiro de 2021): e239213. http://dx.doi.org/10.1136/bcr-2020-239213.
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Anaplastic large cell lymphoma (ALCL), ALK negative (ALK−) is an aggressive lymphoproliferative disorder of mature T lymphocytes characterised by hallmark cells, CD30 positivity and lacking ALK protein expression. ALCL, ALK− has to be differentiated from peripheral T-cell lymphoma-not otherwise specified and classical Hodgkin’s lymphoma. ALK− anaplastic large cell leukaemia should be considered in a patient with a history of ALCL, ALK− presenting with new leukaemia. We report a rare presentation of relapsed ALCL, ALK− with leukaemia after autologous stem cell transplantation in a 57-year-old male. Leukaemia, either as primary presentation or secondary transformation confers worse prognosis in ALCL, ALK− with very few cases reported so far. Emergency resuscitation with leukapheresis and treatment of tumour lysis syndrome along with supportive care should be followed by combination chemotherapy. Brentuximab vedotin and stem cell transplantation are the backbone of treatment for relapsed/refractory disease.
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Lessard, Julie, e Guy Sauvageau. "Bmi-1 determines the proliferative capacity of normal and leukaemic stem cells". Nature 423, n.º 6937 (20 de abril de 2003): 255–60. http://dx.doi.org/10.1038/nature01572.
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Abraham, Sheela A., Lisa E. M. Hopcroft, Emma Carrick, Mark E. Drotar, Karen Dunn, Andrew J. K. Williamson, Koorosh Korfi et al. "Dual targeting of p53 and c-MYC selectively eliminates leukaemic stem cells". Nature 534, n.º 7607 (junho de 2016): 341–46. http://dx.doi.org/10.1038/nature18288.
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