RNA-sequencing of Chronic Myelomonocytic Leukemia and healthy donors bone marrow samples
Ontology highlight
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: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: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.
2012-02-13 | GSE31600 | GEO
Project description:Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm with few treatment options and generally poor prognosis. A defining feature is expansion of classical monocytes, which are responsible for various clinical sequelae and thus represent viable therapeutic targets. Given the near-ubiquity of mutations involving epigenetic regulators, we profiled the epigenome (open chromatin configuration; H3K4-monomethylation; H3K27-acetylation; H3K27/H3K4-trimethylation) and transcriptome of primary CD14+ monocytes from CMML patients and age-matched healthy controls. Compared with healthy monocytes, CMML monocytes displayed heterogeneous but distinct epigenetic and transcriptome signatures. Most epigenetic changes mapped to distal elements, suggesting generalized enhancer dysregulation. We observed strong epigenetic (but not transcriptional) suppression of the NF-κB pathway, suggesting poised potential to repress downstream targets and modulate inflammatory responses. RNA-seq revealed up-regulation of genes involved in the oxidative phosphorylation (OxPhos) machinery, with significantly heightened OxPhos activity of primary CMML monocytes validated in mitochondrial stress tests, highlighting a potentially tractable therapeutic vulnerability. In line with the observed metabolic phenotype of CMML monocytes, unpolarized CMML monocyte-derived macrophages exhibited transcriptional bias towards an M2 (“anti-inflammatory”) phenotype, reflected by an increased Th2/Th1 ratio in comparison with control monocytes. These observations may be germane to the observed clinical heterogeneity and prominent immune dysfunction characteristic of CMML.
2025-01-28 | GSE283203 | GEO
Project description:Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm with few treatment options and generally poor prognosis. A defining feature is expansion of classical monocytes, which are responsible for various clinical sequelae and thus represent viable therapeutic targets. Given the near-ubiquity of mutations involving epigenetic regulators, we profiled the epigenome (open chromatin configuration; H3K4-monomethylation; H3K27-acetylation; H3K27/H3K4-trimethylation) and transcriptome of primary CD14+ monocytes from CMML patients and age-matched healthy controls. Compared with healthy monocytes, CMML monocytes displayed heterogeneous but distinct epigenetic and transcriptome signatures. Most epigenetic changes mapped to distal elements, suggesting generalized enhancer dysregulation. We observed strong epigenetic (but not transcriptional) suppression of the NF-κB pathway, suggesting poised potential to repress downstream targets and modulate inflammatory responses. RNA-seq revealed up-regulation of genes involved in the oxidative phosphorylation (OxPhos) machinery, with significantly heightened OxPhos activity of primary CMML monocytes validated in mitochondrial stress tests, highlighting a potentially tractable therapeutic vulnerability. In line with the observed metabolic phenotype of CMML monocytes, unpolarized CMML monocyte-derived macrophages exhibited transcriptional bias towards an M2 (“anti-inflammatory”) phenotype, reflected by an increased Th2/Th1 ratio in comparison with control monocytes. These observations may be germane to the observed clinical heterogeneity and prominent immune dysfunction characteristic of CMML.
2025-01-28 | GSE283202 | GEO
Project description:Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative overlap neoplasm with few treatment options and generally poor prognosis. A defining feature is expansion of classical monocytes, which are responsible for various clinical sequelae and thus represent viable therapeutic targets. Given the near-ubiquity of mutations involving epigenetic regulators, we profiled the epigenome (open chromatin configuration; H3K4-monomethylation; H3K27-acetylation; H3K27/H3K4-trimethylation) and transcriptome of primary CD14+ monocytes from CMML patients and age-matched healthy controls. Compared with healthy monocytes, CMML monocytes displayed heterogeneous but distinct epigenetic and transcriptome signatures. Most epigenetic changes mapped to distal elements, suggesting generalized enhancer dysregulation. We observed strong epigenetic (but not transcriptional) suppression of the NF-κB pathway, suggesting poised potential to repress downstream targets and modulate inflammatory responses. RNA-seq revealed up-regulation of genes involved in the oxidative phosphorylation (OxPhos) machinery, with significantly heightened OxPhos activity of primary CMML monocytes validated in mitochondrial stress tests, highlighting a potentially tractable therapeutic vulnerability. In line with the observed metabolic phenotype of CMML monocytes, unpolarized CMML monocyte-derived macrophages exhibited transcriptional bias towards an M2 (“anti-inflammatory”) phenotype, reflected by an increased Th2/Th1 ratio in comparison with control monocytes. These observations may be germane to the observed clinical heterogeneity and prominent immune dysfunction characteristic of CMML.
2025-01-28 | GSE283200 | 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