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Gene expression profile at single-cell level of hematopoietic stem and progenitor cells (HSPCs) from individuals with chronic myelomonocytic leukemia (CMML)

ABSTRACT: Myeloblast expansion is a hallmark of disease progression in leukemias and comprises of CD34+ hematopoeitic stem and progeneitor cells. We used single-cell RNA sequencing (scRNAseq) to analyze the transcriptional states of HSPCs in CMML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE211033 | GEO | 2022/11/04

REPOSITORIES: GEO

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Single cell RNA sequencing of chronic myelomonocytic leukemia stem cell

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

RAS Pathway–Mutated Chronic Myelomonocytic Leukemia at the Single Cell Level

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

miRNA expression profiling in a murine model of KrasG12D induced CMML-like MPD

Project description:Mx1-Cre/KrasG12D mice were injected with pIpC to induce a myeloproliferative disease resembling human chronic myelomonocytic leukemia (CMML-like MPD). When the disease was fully developed, CD11b-/Ly6G-/c-Kit+ hematopoietic stem and progenitor cells (HSPCs) were isolated and subjected to miR-microarray expression profiling. pIpC-injected CD11b-/Ly6G-/c-Kit+ HSPCs of age matched wildytpe control mice were used as controls.

2021-01-19 | GSE145083 | GEO

DNA methylation in AZA+/AZA- mesenchymal stromal cells (MSCs) from patients with chronic myelomonocytic leukemia or healthy individuals

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

Proposed diagnostic criteria for classical chronic myelomonocytic leukemia (CMML), CMML variants and pre-CMML conditions.

Project description: Not available

| S-EPMC6886439 | biostudies-literature

Affymetrix SNP array data for chronic myelomonocytic leukemia samples

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

The Transcriptome Of Cmml Monocytes Is Highly Inflammatory And Reflects Leukemia-Specific And Age-Related Alterations

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

SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML).

Project description: Not available

| S-EPMC3580040 | biostudies-literature

RNA-sequencing of Chronic Myelomonocytic Leukemia and healthy donors bone marrow samples

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

TET2 mutations are associated with specific methylation profiles in patients with Chronic Myelomonocytic Leukemia

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

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