Progenitor Hierarchy of Chronic Myelomonocytic Leukemia Identifies Inflammatory Monocytic-Biased Trajectory Linked to Worse Outcomes

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.

Automated summary

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.