期刊
BLOOD CANCER DISCOVERY
卷 3, 期 6, 页码 536-553出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2643-3230.BCD-21-0217
关键词
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资金
- Molecular Genomics Facility, Flow Cytometry Core Facility, and Biostatistics and Bioinformatics Shared Resource at the H. Lee Moffitt Cancer Center and Research Institute, an NCI-designated Comprehensive Cancer Center [P30-CA076292]
- BD Biosciences
- American Cancer Society ACS-IRG award [IRG-17-173-22]
- ACS-RSG award [RSG-19-2015-01-LIB]
- NCI [R37 CA234021-03]
- Myelodysplastic Syndromes (MDS) Foundation
- International Working Group for the Prognosis of MDS (IWG-PM)
- Richard O. Jacobson Foundation
- Moffitt Cancer Center Evolutionary Therapy Center of Excellence
- William G. 'Bill' Bankhead Jr and David Coley Cancer Research Program [20B06]
Our study reveals the differentiation trajectories of CD34+ hematopoietic stem and progenitor cells (HSPC) in chronic myelomonocytic leukemia (CMML) and identifies the monocytic-biased trajectory as an adverse feature associated with poorer outcomes. We find that cytokine receptor diversity is elevated in GMP-like cells, which contributes to the monocytic-biased state. Hypomethylating agents and hematopoietic stress are found to affect the monocytic-biased state. Our findings suggest that deconvoluting HSPC compartments and exploring therapeutic strategies to mitigate the monocytic-biased differentiation trajectory should be further investigated in other myeloid neoplasms.
Myeloblast expansion is a hallmark of disease progression and comprises CD34+ hematopoietic stem and progenitor cells (HSPC). How this compartment evolves during disease progression in chronic myeloid neoplasms is unknown. Using single-cell RNA sequencing and high-parameter fl ow cytometry, we show that chronic myelomonocytic leukemia (CMML) CD34+ HSPC can be classifi ed into three differentiation trajectories: monocytic, megakaryocyte-erythroid progenitor (MEP), and normal-like. Hallmarks of monocytic-biased trajectory were enrichment of CD120b+ infl ammatory granulocyte-macrophage progenitor (GMP)-like cells, activated cytokine receptor signaling, phenotypic hematopoietic stem cell (HSC) depletion, and adverse outcomes. Cytokine receptor diversity was generally an adverse feature and elevated in CD120b + GMPs. Hypometh-ylating agents decreased monocytic-biased cells in CMML patients. Given the enrichment of RAS path-way mutations in monocytic-biased cells, NRAS-competitive transplants and LPS-treated xenograft models recapitulated monocytic-biased CMML, suggesting that hematopoietic stress precipitates the monocytic-biased state. Deconvolution of HSPC compartments in other myeloid neoplasms and identifying therapeutic strategies to mitigate the monocytic-biased differentiation trajectory should be explored. SIGNIFICANCE: Our findings establish that multiple differentiation states underlie CMML disease progression. These states are negatively augmented by infl ammation and positively affected by hypo-methylating agents. Furthermore, we identify HSC depletion and expansion of GMP-like cells with increased cytokine receptor diversity as a feature of myeloblast expansion in infl ammatory chronic myeloid neoplasms.
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