Bone marrow failure (BMF) in Fanconi anemia (FA) patients results from dysfunctional hematopoietic stem and progenitor cells (HSPCs). To identify determinants of BMF, we performed single-cell transcriptome profiling of primary HSPCs from FA patients. In addition to overexpression of p53 and TGF-β pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing high levels of TP53 or MYC in FA bone marrow (BM). Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced the clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing that MYC promotes proliferation while increasing DNA damage. MYC-high HSPCs showed significant downregulation of cell adhesion genes, consistent with enhanced egress of FA HSPCs from bone marrow to peripheral blood. We speculate that MYC overexpression impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow.

范可尼贫血 (FA) 患者的骨髓衰竭 (BMF) 是由功能失调的造血干细胞和祖细胞 (HSPC) 引起的。为了确定 BMF 的决定因素，我们对来自 FA 患者的原代 HSPC 进行了单细胞转录组分析。除了 p53 和 TGF-β 通路基因的过度表达外，我们还发现了高水平的MYC表达。我们相应地观察到在 FA 骨髓 (BM) 中表达高水平TP53或MYC的不同 HSPC 亚群共存。用 BET 溴结构域抑制剂 (+)-JQ1 抑制 MYC 表达降低了 FA 患者 HSPC 的克隆形成潜力，但挽救了 FA 小鼠 HSPC 的生理和遗传毒性应激，表明 MYC 促进增殖，同时增加 DNA 损伤。我的C-高 HSPC 表现出细胞粘附基因的显着下调，这与 FA HSPC 从骨髓到外周血的流出增加一致。我们推测MYC过表达会损害 FA 患者的 HSPC 功能，并导致 FA 骨髓衰竭。