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• W4283360895 abstract "Background: Most patients (pts) with chronic myelomonocytic leukemia (CMML) have incomplete or transient responses to hypomethylating agent (HMA) therapy. CMML cases driven by mutations in RAS pathway signaling genes or ASXL1 have a higher risk of failure and progression to acute myeloid leukemia (AML). Development of effective alternative therapies has been delayed, owing to an incomplete understanding of how different hematopoietic populations contributes to disease maintenance and progression. Aims: We aimed to dissect the cellular and molecular mechanisms underpinning CMML maintenance and progression in RAS mutant CMML. Methods: We performed single-cell RNA sequencing (scRNA-seq) analysis of lineage-negative (Lin-) CD34+ hematopoietic stem and progenitor cells (HSPCs) and BM mononuclear cells (MNCs) isolated from RAS pathway mutant CMML pts (n=5 and 6, respectively) and age-matched healthy donors (HD; n=2 and 3, respectively). CMML samples were obtained at the time of diagnosis and HMA failure. Additionally, we performed scATAC-seq analysis of Lin-CD34+ HPSCs isolated at the times of diagnosis and progression (n=1). Results: Our analysis revealed that CMML HSPCs had a predominantly granulomonocytic differentiation route with increased frequencies of myeloid-monocytic progenitors, at the expense of hematopoietic stem cells (HSCs) (Fig 1a), and upregulated expression of genes involved in the oxidative phosphorylation, type I interferon (IFN) and IFNg pathways. Consistent with these results, scRNA-seq analysis of MNCs revealed expanded populations of myelomonocytic progenitors and monocytes and upregulated expression of genes involved in IFNg response and NF-kB activation (Fig 1b), along with upregulation of the NF-kB transcriptional effector BCL2A1 (Fig 1c). Assessment of ligand-receptor interactions using the CellPhoneDB repository identified that CMML monocytes established a high number of cell-cell interactions (n=638) with dendritic cells, NK cells, and HSPCs via chemokines, cytokines, and inhibitory molecules known to induce NF-kB signaling and NK-cell exhaustion. Disease progression was associated with expansion of lympho-myeloid progenitors (LMPPs) (Fig 1d) characterized by the highest levels of IFNg response, NF-kB survival signaling, and cell cycle regulators. scATAC-seq of Lin-CD34+ confirmed higher activity of transcriptional factors associated with monocytic differentiation and NF-kB signaling (Fig 1e-f). Accordingly, scRNA-seq analysis of MNCs showed increased frequencies of HSPCs and myelomonocytic precursors, a reduction of T cells (Fig 1f), and emergence of a monocyte population characterized by the highest expression of NF-kB signaling and its effectors MCL1 and BCL2A1. BCL2A1 protein expression at progression was confirmed by immunohistochemistry (Fig 1g). CellPhoneDB analysis identified a high number of cell-cell interactions (n=2978) involving cytokines, chemokines, and surface proteins known to elicit NF-kB activation and immune evasion between expanded monocytes, LMPPs, myelomonocytic precursors, and immune cells during progression. Image:Summary/Conclusion: Our data suggests that CMML is maintained through metabolically active HSPCs, which leads to monocytes’ reprograming and survival through NF-kB signaling activation. We showed that disease progression arises from the expansion of NF-kB dependent immature myeloid progenitors, which leads to therapy resistance and immune evasion. This study has implications for the development of therapies targeting downstream effectors of NF-kB–mediated survival pathway to overcome treatment failure. In vitro validation is ongoing." @default.
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• W4283360895 date "2022-06-01" @default.
• W4283360895 modified "2023-10-15" @default.
• W4283360895 title "S160: MOLECULAR DETERMINANTS OF DISEASE PROGRESSION AFTER HYPOMETHYLATING AGENT THERAPY IN RAS PATHWAY MUTANT CHRONIC MYELOMONOCYTIC LEUKEMIA AT THE SINGLE-CELL LEVEL" @default.
• W4283360895 doi "https://doi.org/10.1097/01.hs9.0000843532.08926.df" @default.
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