| Literature DB >> 32997960 |
Alfredo Rodríguez1, Kaiyang Zhang2, Anniina Färkkilä3, Jessica Filiatrault4, Chunyu Yang4, Martha Velázquez4, Elissa Furutani5, Devorah C Goldman6, Benilde García de Teresa7, Gilda Garza-Mayén7, Kelsey McQueen4, Larissa A Sambel4, Bertha Molina7, Leda Torres7, Marisol González7, Eduardo Vadillo8, Rosana Pelayo9, William H Fleming6, Markus Grompe6, Akiko Shimamura5, Sampsa Hautaniemi2, Joel Greenberger10, Sara Frías11, Kalindi Parmar4, Alan D D'Andrea12.
Abstract
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.Entities:
Keywords: CXCR4; DNA damage; Fanconi anemia; MYC; bone marrow failure; genotoxic stress; hematopoietic stem cells; p53; physiological stress; single-cell RNA sequencing
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Year: 2020 PMID： 32997960 PMCID： PMC7796920 DOI： 10.1016/j.stem.2020.09.004
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633