Affymetrix SNP array data for chronic myelomonocytic leukemia samples
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE67460 | GEO | 2015/12/01
SECONDARY ACCESSION(S): PRJNA279998
REPOSITORIES: GEO
Similar Datasets
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: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: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:RNA-seq of bone marrow samples of chronic myelomonocytic leukemia (CMML) patients and healthy donors to identify the molecular DNA repair pathways involved in CMML pathogenic
2020-08-07 | GSE102312 | GEO
Project description:PURPOSE: To evaluate frequency, biological features and clinical relevance of RUNX1 mutations in acute myeloid leukemia (AML). PATIENTS AND METHODS: Diagnostic samples from 945 patients (18 to 60 years) were analyzed for RUNX1 mutations. In a subset of cases (n=269) microarray gene expression analysis was performed. RESULTS: Fifty-nine RUNX1 mutations were identified in 53 of 945 (5.6%) cases, predominantly in exons 3 (n=11), 4 (n=10) and 8 (n=23). RUNX1 mutations clustered in the intermediate-risk cytogenetic group (46/640, 7.2%; cytogenetically normal, 34/538, 6.3%), they were less frequent in adverse-risk cytogenetics (5/109, 4.6%), and absent in core-binding-factor AML (0/77) and acute promyelocytic leukemia (0/61); RUNX1 mutations were associated with MLL-partial tandem duplications (p=0.0007) and IDH1/IDH2 mutations (p=0.03), inversely correlated with NPM1 (p<0.0001) and in trend with CEBPA (p=0.10) mutations. RUNX1 mutations were characterized by a distinct gene expression pattern; this RUNX1 mutation-derived signature was not exclusive for the mutation, but also included mostly adverse-risk AML [eg, 7q-, -7, inv(3) or t(3;3)]. RUNX1 mutations predicted for resistance to chemotherapy (rates of refractory disease 30% and 19%, p=0.047, for RUNX1-mutated and wildtype patients, respectively), as well as inferior event-free survival (EFS; p<0.0001), relapse-free survival (RFS, p=0.022), and overall survival (p=0.051). In multivariable analysis, RUNX1 mutations were an independent prognostic marker for shorter EFS (p=0.007). Explorative subgroup analysis revealed that allogeneic hematopoietic stem cell transplantation had a favorable impact on RFS in RUNX1-mutated patients (p<0.0001). CONCLUSION: AML with RUNX1 mutations exhibit distinct biological properties and are associated with resistance to therapy and inferior outcome. A total of 269 RNA samples derived from adult AML patients were provided by the German Austrian AML Study Group (AMLSG) [AMLSG trial AML HD98A (ClinicalTrials.gov Identifier: NCT00146120)]. Conventional cytogenetic banding, and FLT3, CEBPA and NPM1 mutational analysis were performed as previously described (Schlenk et al., N Engl J Med 2008). Detailed clinical, cytogenetic and molecular cytogenetic information are also provided in the supplementary information. Following enrichment, all samples contained at least 80% leukemic cells. Gene expression profiling (GEP) was performed as previously described (Bullinger et al., N Engl J Med 2004).
2010-12-31 | E-GEOD-23312 | biostudies-arrayexpress
Project description:Lenalidome is a drug especially effective in low risk myelodysplastic syndromes (MDS) with isolated 5q deletion. However, 25% of the patients did not respond. TP53 mutations have been described to play a role in the disease progression, and karyotypic complexity also has an important impact in the outcome. We selected 53 MDS patients with 5q deletion and treated with lenalidomide and we studied by the following techniques: conventional G-banding cytogenetics (CC), single nucleotide polymorphism arrays (SNP-A) and sequencing, in order to assess their impact on treatment response and disease progression. Low karyotypic complexity (by CC), a high baseline platelet count (>280x103/L) and TP53 unmutated gene status are associated with the achievement of hematological response (P=0.005, P=0.008 and P=0.057, respectively). In a multivariate model, the most important predictors for lenalidomide failure are karyotypic complexity (P=0.014) and a platelet count below 280x103/L (P=0.042). Additionally, none of the TP53 mutated cases achieved complete cytogenetics response. Nevertheless, inclusion of defects by SNP-A did not allow for a better separation of responders and non responders. These findings constitute a useful reference data to be considered before lenalidomide treatment enrollment.
2013-07-01 | GSE35656 | 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 myelomonocytic leukemia (CMML) is an aggressive myeloid neoplasm of older individuals characterized by persistent monocytosis. Somatic mutations in CMML are heterogeneous and only partially explain the variability in clinical outcomes. Recent data suggest that cardiovascular morbidity is increased in CMML and contributes to reduced survival. Clonal hematopoiesis of indeterminate potential (CHIP), the presence of mutated blood cells in hematologically normal individuals, is a precursor of age-related myeloid neoplasms and associated with increased cardiovascular risk. To isolate CMML-specific alterations from those related to aging, we performed RNA sequencing and DNA methylation profiling on purified monocytes from CMML patients and from age-matched (old) and young healthy controls. We found that the transcriptional signature of CMML monocytes is highly pro-inflammatory, with upregulation of multiple inflammatory pathways, including tumor necrosis factor, IL-6 and IL-17 signaling, while age per se does not significantly contribute to this pattern. We observed no consistent correlations between aberrant gene expression and CpG island methylation, suggesting that pro-inflammatory signaling in CMML monocytes is governed by multiple and complex regulatory mechanisms. We propose that pro-inflammatory monocytes may contribute to cardiovascular morbidity in CMML patients, and promote progression by selection of mutated cell clones. Our data raise questions whether asymptomatic CMML patients may benefit from monocyte-depleting or anti-inflammatory therapies.
2019-10-24 | GSE135902 | GEO