RNA-sequencing of Chronic Myelomonocytic Leukemia and healthy donors bone marrow samples
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE102312 | GEO | 2020/08/07
REPOSITORIES: GEO
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Project description:Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic disorder with heterogeneous clinical, morphological and genetic characteristics. Clonal cytogenetic abnormalities are found in 20-30% of patients with CMML. Patients with low risk cytogenetic features (normal karyotype and isolated loss of Y chromosome) account for approximately 80% of CMML patients and often fall into the low risk categories of CMML prognostic scores. SNP-A were performed in 82 CMML patients with low risk karyotypes and uninformative results for conventional G-banding cytogenetics (CC).
2015-12-01 | GSE67460 | GEO
Project description:RAS pathway mutations, which are present in 30% of patients with chronic myelomonocytic leukemia (CMML) at diagnosis, confer a high risk of resistance to and progression after hypomethylating agent (HMA) therapy, the current standard of care for the disease. Using single-cell, multi-omics technologies, we sought to dissect the biological mechanisms underlying the initiation and progression of RAS pathway–mutated CMML. We found that RAS pathway mutations induced the transcriptional reprogramming of hematopoietic stem and progenitor cells (HSPCs), which underwent proliferation and monocytic differentiation in response to cell-intrinsic and -extrinsic inflammatory signaling that also impaired immune cells’ functions. HSPCs expanded at disease progression and relied on the NF-KB pathway effector MCL1 to maintain their survival, which explains why patients with RAS pathway–mutated CMML do not benefit from BCL2 inhibitors such as venetoclax. Our study has implications for developing therapies to improve the survival of patients with RAS pathway–mutated CMML.
2024-04-21 | GSE218390 | GEO
Project description:Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes implicated in epigenetic mechanisms such as TET2 or EZH2. We have performed genome-wide methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis enrichment in a gene network centered in PLC, JNK and ERK, a recently described pathway involved in CMML was found, suggesting the potential role of epigenetics in the regulation of these pathways. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65.2%), 4 patients (16.6%) and 1 patient (4.1%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with the presence of altered karyotypes a known prognostic factor in CMML. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile. 24 samples of CMML patients, 4 healthy donor Peripheral Blood samples and 4 healthy donor Bone Marror samples
2012-02-13 | E-GEOD-31600 | biostudies-arrayexpress
Project description:Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes implicated in epigenetic mechanisms such as TET2 or EZH2. We have performed genome-wide methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis enrichment in a gene network centered in PLC, JNK and ERK, a recently described pathway involved in CMML was found, suggesting the potential role of epigenetics in the regulation of these pathways. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65.2%), 4 patients (16.6%) and 1 patient (4.1%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with the presence of altered karyotypes a known prognostic factor in CMML. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.
2012-02-13 | GSE31600 | GEO
Project description:Chromosomal abnormalities are detected in 20-30% of patients with chronic myelomonocytic leukemia (CMML) and correlate with prognosis. Epigenetic abnormalities are frequent in CMML, including mutations in DNA methylation and histone-modifying enzymes, but the methylation profile is not well characterized in these patients. In this study we performed DNA methylation microarrays in 65 CMML patients and 10 healthy controls. Differential methylation analysis between patients and controls allowed us to identify abnormalities in DNA methylation including hypermethylated genes, large genome regions with aberrant DNA methylation and altered cellular pathways. Hierarchical cluster analysis identified two main clusters that associated with the clinical, biological and genetic features of patients. Group 1 was enriched in patients that presented with adverse clinical and biological characteristics and that had a poorer overall survival and progression free survival. In addition, significant differences in DNA methylation was observed between patients with low risk and intermediate/high risk karyotypes and between TET2 mutant and wild-type patients. These results demonstrate that DNA methylation is altered in CMML and is associated with distinct biological and clinical features. Furthermore, these results may provide a useful basis for identifying new therapeutic targets.
2017-11-17 | GSE105420 | GEO
Project description:We report the gene expression of human chronic myelomonocytic leukemia by performing whole transcriptome shotgun sequencing of peripheral blood mononuclear cells of patients with chronic myelomonocytic leukemia.
2020-08-14 | GSE156209 | GEO
Project description:The respective role of genetic and epigenetic heterogeneity in the functional diversity of cells that compose human malignancies remains poorly understood. This question is addressed in chronic myelomonocytic leukemia (CMML), a myeloid neoplasm in which clinical diversity contrasts with a limited genetic heterogeneity. By reprogramming CMML-patient and healthy donor CD34-positive cells, we generated induced pluripotent cell clones (iPSC). In one of the patients, we captured a part of the genetic heterogeneity of the leukemic clone and analyzed five iPSCs with two distinct genetic backgrounds, i.e. with and without KRASG12D mutation. Hematopoietic differentiation of these clones recapitulated the main features of the patient disease, including overproduction of granulomonocytes and dysmegakaryopoiesis. These analyses also disclosed significant discrepancies in the behavior as well as the DNA methylation pattern of hematopoietic cells derived from iPSCs with similar genetic background. Introduction of SRSF2P95H mutation in a KRAS-mutated iPSC partially suppressed the functional and epigenetic gap with the other KRAS-mutated clone. Despite the similar functional behavior of these two clones, only the SRSF2P95H clone responded to low doses of the hypomethylating agent decitabine by restoration of a more balanced production of hematopoietic cells. These analyses unravel additional levels of intraclonal heterogeneity beyond the coding mutations, which may also modulate individual cell response to treatment.
2020-04-14 | GSE114115 | GEO
Project description:DNA methylation is a fundamental epigenetic modification regulating gene expression. Aberrant DNA methylation may be involved in the transcriptionally/functionally altered CMML-MSCs. However, understanding the overall DNA methylation profile in MSCs and its changes after the intervention of demethylating drugs such as AZA is still lacking. In this present study, In vitro expanded MSCs from CMML patients (n=10) and healthy individuals (n=5) were treated with AZA or DMSO, and then used for DNA methylation profiling (EPIC) respectively. A total of 30 MSC samples were included. MSCs. Our study reveals that MSCs from different individual cohorts (healthy vs. CMML) exhibit significantly different sensitivity and reactivity to AZA. AZA treatment in vitro modulates aberrant DNA methylation profiles in CMML-MSCs and restores their impaired support for healthy hematopoiesis. Our study shows that the therapeutic effect of AZA on CMML patients is not limited to its inhibitory effect on malignant clones, but also manifested in its regulatory effect on the damaged bone marrow stromal microenvironment. Targeted improvement of bone marrow microenvironment may be a potential way to improve and restore normal hematopoiesis in patients with CMML.
2022-12-22 | GSE221269 | GEO
Project description:Chronic myelomonocyticleukemia (CMML) is a clinically heterogeneous stem cell malignancy with overlapping features of myelodysplasiaand myeloproliferation. CMML is further subclassified according to percentage of leukemic blasts present in blood or bone marrow, reflecting its intrinsic tendency to progression towards acute myeloid leukemia. Over 90% of CMML patients carry founding mutations in epigenetic and/or splicing genes, which typically involve the primitive stem cell compartment. Thus, transcriptional dysregulation at the stem cell level is likely fundamental to disease onset and progression. However, the critical early hematopoietic stem and progenitor cell (HSPC) subpopulation has not been studied in CMML. We performed single cell RNA sequencing on>6,800 Lin-CD34+CD38-primitive HSPCs from seven CMML patients and three healthy controls. We found substantial inter-and intra-patient heterogeneity, with CMML stem cells displaying distinct transcriptional programs, differentiation potential and cellular signaling pathway priming. Pseudotime analyses revealed that CMML-1/CMML-2 HSPCs have distinct cellular trajectories, indicating that transformation events initiate early within the hematopoietic hierarchy and suggesting against a simple linear clonal evolution dynamic in acute leukemic transformation. We further identified several transcription factors uniquely active in distinct sample subsets. Together our findings provide novel insights into the CMML stem cell compartment, revealing an unexpected degree of transcriptional and subclonal heterogeneity and highlighting early mediators of disease initiation and transformation, of potential translational importance
2020-08-03 | E-MTAB-8884 | biostudies-arrayexpress
Project description:Transcriptome of chronic myelomonocytic leukemia
| PRJNA657050 | ENA