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Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML [Bisulfite-Seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE165302 | GEO | 2021/01/23

REPOSITORIES: GEO

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Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML [RNA-Seq]

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.

2021-01-23 | GSE165304 | GEO

Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

Project description:Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML

| PRJNA694040 | ENA

Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML [RNA-Seq]

Project description:Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML [RNA-Seq]

| PRJNA694045 | ENA

Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML [Bisulfite-Seq]

Project description:Cytokine-like protein 1-induced survival of monocytes suggests a combined strategy targeting MCL1 and MAPK in CMML [Bisulfite-Seq]

| PRJNA694046 | ENA

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

ChIP-seq of EGR1 in human primary unstimulated monocytes and in unstimulated human monocytes from three CMML patients

Project description:Identification of EGR1 chromatin localization in human primary monocytes (2 donors), in human primary monocytes from 2 CMML patients with TET2 truncating mutations (high VAF) and in human primary monocytes from 1 CMML patients with TET2 truncating mutations with low VAF.

2021-11-15 | E-MTAB-11132 | biostudies-arrayexpress

Osteosarcoma uses host-derived growth factors to drive ERK phosphorylation and MCL1 expression to survive in the metastatic environment

Project description:Purpose: For patients with osteosarcoma, disease-related mortality most often results from lung metastasis—a phenomenon shared with many solid tumors. While established metastatic lesions behave aggressively, very few of the tumor cells that reach the lung will survive. By identifying mechanisms that facilitate survival of disseminated tumor cells, we can develop therapeutic strategies that prevent and treat metastasis. Methods: We analyzed scRNAseq data from murine metastasis-bearing lungs to interrogate changes in both host and tumor cells during colonization. We used these data to elucidate pathways that become activated in cells that survive dissemination and identify candidate host-derived signals that drive activation. We validated these findings through live cell reporter systems, immunocytochemistry, and fluorescent immunohistochemistry. We then validated the functional relevance of key candidates using pharmacologic inhibition in models of metastatic osteosarcoma. Results: Expression patterns suggest that the MAPK pathway is significantly elevated in early and (to a lesser degree) established metastases. MAPK activity correlates with expression of anti-apoptotic genes, especially MCL1. Niche cells produce growth factors that increase ERK phosphorylation and MCL1 expression in tumor cells. Both early and established metastases are vulnerable to MCL1 inhibition, but not MEK inhibition in vivo. Combining MCL1 inhibition with chemotherapy both prevented colonization and eliminated established metastases in murine models of osteosarcoma. Conclusion: Niche-derived growth factors drive MAPK activity and MCL1 expression in osteosarcoma, promoting metastatic colonization. Although later metastases produce less MCL1, they remain dependent on it. MCL1 is a promising target for clinical trials in both human and canine patients.

2024-05-03 | GSE234614 | GEO

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

Project description: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.

2022-11-04 | GSE211033 | GEO

MCL1 is deregulated in subgroups of diffuse large B-cell lymphoma

Project description:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)) [PMID 23257783]. Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples [GSE11318] and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs. This GEO dataset is comprised of aCGH measurements for DLBCL cell lines, which are used in the above-mentioned paper. Cell lines were measured against the DNA of a healthy male donor who in turn was measured against a pool of healthy DNAs to correct for individual CNVs of the donor.

2013-01-04 | E-GEOD-43272 | biostudies-arrayexpress

Identification of human MCL1 acetylation

Project description:The anti-apoptotic MCL1 protein is a member of the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 protein is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. We attempted to identify acetylation as another critical post-translational modification regulating MCL1 protein stability. To this end, 293T cells were transfected with HA-humanMCL1 and Myc-p300. The whole-cell lysates were immunoprecipitated with anti-HA agarose beads. The immunoprecipitated material was resolved by SDS-PAGE, and the MCL1 band was excised for tryptic digestion followed by the MS analysis.

2021-10-14 | MSV000088231 | MassIVE

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