MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.
MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.
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DOI：
10.1016/j.stem.2020.09.004
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发表时间：
2021-01-07
期刊：
影响因子：
23.9
通讯作者：
D'Andrea AD
中科院分区：
文献类型：
--
作者：
Rodríguez A;Zhang K;Färkkilä A;Filiatrault J;Yang C;Velázquez M;Furutani E;Goldman DC;García de Teresa B;Garza-Mayén G;McQueen K;Sambel LA;Molina B;Torres L;González M;Vadillo E;Pelayo R;Fleming WH;Grompe M;Shimamura A;Hautaniemi S;Greenberger J;Frías S;Parmar K;D'Andrea AD
范可尼贫血（FA）患者的骨髓衰竭是由造血干细胞和祖细胞（HSPC）功能障碍引起的。为了确定骨髓衰竭的决定因素，我们对FA患者的原代HSPC进行了单细胞转录组分析。除了p53和TGFβ通路基因的过表达外，我们还发现了高水平的MYC表达。我们相应地观察到FA骨髓中表达高水平TP 53或MYC的不同HSPC亚群的共存。用BET布罗莫结构域抑制剂（+）-JQ 1抑制MYC表达降低了FA患者HSPC的克隆形成潜力，但挽救了来自FA小鼠的HSPC中的生理和遗传毒性应激，表明MYC促进增殖，同时增加DNA损伤。MYC-高HSPC显示细胞粘附基因的显著下调与FA HSPC从骨髓到外周血的增强的流出一致。因此，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。Rodriguez及其同事证明，MYC在范可尼贫血（FA）患者的造血干细胞和祖细胞（HSPC）中上调。一方面，MYC抵消了FA骨髓中p53和TGFβ介导的生长抑制。另一方面，MYC表达抑制FA HSPCs的复制和基因毒性应激。
Bone marrow failure in Fanconi anemia (FA) patients results from dysfunctional hematopoietic stem and progenitor cells (HSPCs). To identify determinants of bone marrow failure, we performed single-cell transcriptome profiling of primary HSPCs from FA patients. In addition to overexpression of p53 and TGFβ pathway genes, we identified high levels of MYC expression. We correspondingly observed coexistence of distinct HSPC subpopulations expressing either high levels of TP53 or MYC in FA bone marrow. Inhibiting MYC expression with the BET bromodomain inhibitor (+)-JQ1 reduced clonogenic potential of FA patient HSPCs but rescued physiological and genotoxic stress in HSPCs from FA mice, showing 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 therefore impairs HSPC function in FA patients and contributes to exhaustion in FA bone marrow. Rodriguez and colleagues demonstrate that MYC is upregulated in hematopoietic stem and progenitor cells (HSPCs) from Fanconi anemia (FA) patients. On one hand, MYC counteracts the p53 and TGFβ-mediated growth suppression in FA bone marrow. On the other hand, MYC expression worsens the replication and genotoxic stress of FA HSPCs.
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影响因子：
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