Department of Radiation Oncology and Center for DNA Damage and Repair, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Laboratorio de Citogenética, Instituto Nacional de Pediatría, Mexico City 04530, Mexico.
Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, Helsinki 00014, Finland.
Cell Stem Cell. 2021 Jan 7;28(1):33-47.e8. doi: 10.1016/j.stem.2020.09.004. Epub 2020 Sep 29.
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）是由于造血干祖细胞（HSPCs）功能障碍所致。为了确定 BMF 的决定因素，我们对 FA 患者的原代 HSPC 进行了单细胞转录组谱分析。除了 p53 和 TGF-β 通路基因的过表达外，我们还发现了 MYC 表达水平升高。我们相应地观察到 FA 骨髓（BM）中存在表达高水平 TP53 或 MYC 的不同 HSPC 亚群共存。用 BET 溴结构域抑制剂（+）-JQ1 抑制 MYC 表达可降低 FA 患者 HSPC 的集落形成潜力，但可挽救 FA 小鼠 HSPC 中的生理和遗传毒性应激，表明 MYC 促进增殖的同时增加 DNA 损伤。MYC-高 HSPCs 表现出细胞黏附基因的显著下调，与 FA HSPCs 从骨髓向外周血的增强迁出一致。我们推测，MYC 过表达会损害 FA 患者 HSPC 的功能，并导致 FA 骨髓衰竭。
