The Transcriptome Of Cmml Monocytes Is Highly Inflammatory And Reflects Leukemia-Specific And Age-Related Alterations
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ABSTRACT:
PROVIDER: PRJNA560516 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9988010.fastq.gz | Fastqsanger.gz | |||
| SRR9988020.fastq.gz | Fastqsanger.gz | |||
| SRR9988030.fastq.gz | Fastqsanger.gz | |||
| SRR9988040.fastq.gz | Fastqsanger.gz | |||
| SRR9988011.fastq.gz | Fastqsanger.gz |
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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
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 proinflammatory, with upregulation of multiple inflammatory pathways, including tumor necrosis factor and interleukin (IL)-6 and -17 signaling, whereas 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 proinflammatory signaling in CMML monocytes is governed by multiple and complex regulatory mechanisms. We propose that proinflammatory monocytes contribute to cardiovascular morbidity in CMML patients and promote progression by selection of mutated cell clones. Our data raise questions of whether asymptomatic patients with CMML benefit from monocyte-depleting or anti-inflammatory therapies.
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Project description:Mouse models of chronic myeloid malignancies suggest that targeting mature cells of the malignant clone disrupts feedback loops that promote disease expansion. Here, we show that, in chronic myelomonocytic leukemia (CMML), monocytes that accumulate in the peripheral blood show a decreased propensity to die by apoptosis. BH3 profiling demonstrates their addiction to MCL1 (myeloid cell leukemia-1), which can be targeted with the small molecule inhibitor S63845. RNA sequencing and DNA methylation pattern analysis both point also to the implication of the MAPK (mitogen-activated protein kinase) pathway in the resistance of CMML monocytes to death and reveal an autocrine pathway in which the secreted cytokine CYTL1 (Cytokine-like protein 1) promotes ERK (extracellular signal-regulated kinase) activation through CCR2 (C-C chemokine receptor type 2). Combined MAPK and MCL1 inhibition restores apoptosis of CMML patient monocytes and reduces the expansion of patient-derived xenografts in mice. These results designate the combined inhibition of MCL1 and MAPK as a promising approach to slow down CMML progression by inducing leukemic monocyte apoptosis.
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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.
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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.
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