Summary

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.

Overall design

Expression profiles of single cells from seven Fanconi Anemia patients and five healthy donors.

Contributors

Alfredo Rodríguez 1, Kaiyang Zhang 2, Anniina Färkkilä 3, Jessica Filiatrault 4, Chunyu Yang 4, Martha Velázquez 4, Elissa Furutani 5, Devorah C Goldman 6, Benilde García de Teresa 7, Gilda Garza-Mayén 7, Kelsey McQueen 4, Larissa A Sambel 4, Bertha Molina 7, Leda Torres 7, Marisol González 7, Eduardo Vadillo 8, Rosana Pelayo 9, William H Fleming 6, Markus Grompe 6, Akiko Shimamura 5, Sampsa Hautaniemi 2, Joel Greenberger 10, Sara Frías 11, Kalindi Parmar 4, Alan D D'Andrea 12

Contact

alan_dandrea@dfci.harvard.edu.(Alan D D'Andrea)