MiRNA expression profiling in a murine model of KrasG12D induced CMML-like MPD
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ABSTRACT:
PROVIDER: PRJNA605975 | ENA |
REPOSITORIES: ENA
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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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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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Project description:Sexual dimorphisms are well recognized in various cardiac diseases, including myocardial infarction (MI). MI develops later in women, but once established, it contributes more persistent symptoms and higher mortality than in men. Similar observations have been reported in murine model of MI. Although mRNA-level sexual dimorphism of MI have been reported, whether miRNA transcriptome also confers such dimorphism remains unknown. Comprehensive understanding of the mRNA- and miRNA-level genetic programs underlying the heart sexual dimorphisms will expectedly improve clinical outcome by facilitating the development of gender specific treatment strategies. Here, by conducting miRNA microarray analysis of murine MI model samples, we set out to characterize the heart sexual dimorphisms at the level of miRNA transcriptome The left anterior descending (LAD) coronary artery of mice aged 10 weeks was surgically ligated to create extensive MI. The ventricular septum of the areas at risk of ischemia was sampled on post-operative day 28. Total RNA was extracted using Sepasol solution (Sepasol-RNA I super G, nakalai tesque, Japan), and microarray analysis was performed using Affymetrix GeneChip® miRNA 3.0 Arrays
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