J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida.
University of Florida Health Cancer Center, University of Florida, Gainesville, Florida.
Blood Cancer Discov. 2022 Nov 2;3(6):536-553. doi: 10.1158/2643-3230.BCD-21-0217.
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 flow cytometry, we show that chronic myelomonocytic leukemia (CMML) CD34+ HSPC can be classified into three differentiation trajectories: monocytic, megakaryocyte-erythroid progenitor (MEP), and normal-like. Hallmarks of monocytic-biased trajectory were enrichment of CD120b+ inflammatory 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. Hypomethylating agents decreased monocytic-biased cells in CMML patients. Given the enrichment of RAS pathway 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.
Our findings establish that multiple differentiation states underlie CMML disease progression. These states are negatively augmented by inflammation and positively affected by hypomethylating agents. Furthermore, we identify HSC depletion and expansion of GMP-like cells with increased cytokine receptor diversity as a feature of myeloblast expansion in inflammatory chronic myeloid neoplasms. This article is highlighted in the In This Issue feature, p. 476.
骨髓细胞增生是疾病进展的标志，包括 CD34+造血干细胞和祖细胞（HSPC）。在慢性髓系肿瘤中，这一区域在疾病进展过程中是如何演变的尚不清楚。我们使用单细胞 RNA 测序和高参数流式细胞术表明，慢性粒单核细胞白血病（CMML）CD34+HSPC 可分为三个分化轨迹：单核细胞、巨核细胞-红细胞祖细胞（MEP）和正常样。单核细胞偏向轨迹的特征是富含 CD120b+炎性粒细胞-巨噬细胞祖细胞（GMP）样细胞、激活的细胞因子受体信号、表型造血干细胞（HSC）耗竭和不良结局。细胞因子受体多样性通常是一个不利特征，并且在 CD120b+GMP 中升高。低甲基化剂可减少 CMML 患者的单核细胞偏向细胞。鉴于单核细胞偏向细胞中 RAS 通路突变的富集，NRAS 竞争性移植和 LPS 处理的异种移植模型再现了单核细胞偏向的 CMML，表明造血应激引发了单核细胞偏向状态。在其他髓系肿瘤中对 HSPC 区室进行去卷积并确定减轻单核细胞偏向分化轨迹的治疗策略应该进行探索。
我们的研究结果确立了多种分化状态是 CMML 疾病进展的基础。这些状态受到炎症的负面影响和低甲基化剂的积极影响。此外，我们发现 HSC 耗竭和具有增加的细胞因子受体多样性的 GMP 样细胞的扩增是炎症性慢性髓系肿瘤中骨髓细胞增生的特征。本文在本期特色文章中重点介绍，第 476 页。
