MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia

Alfredo Rodríguez, Kaiyang Zhang, Anniina Färkkilä, Jessica Filiatrault, Chunyu Yang, Martha Velázquez, Elissa Furutani, Devorah C. Goldman, Benilde García de Teresa, Gilda Garza-Mayén, Kelsey McQueen, Larissa A. Sambel, Bertha Molina, Leda Torres, Marisol González, Eduardo Vadillo, Rosana Pelayo, William H. Fleming, Markus Grompe, Akiko ShimamuraSampsa Hautaniemi, Joel Greenberger, Sara Frías, Kalindi Parmar, Alan D. D'Andrea

Research output: Contribution to journalArticlepeer-review

33 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)33-47.e8
JournalCell Stem Cell
Volume28
Issue number1
DOIs
StatePublished - Jan 7 2021

Keywords

  • CXCR4
  • DNA damage
  • Fanconi anemia
  • MYC
  • bone marrow failure
  • genotoxic stress
  • hematopoietic stem cells
  • p53
  • physiological stress
  • single-cell RNA sequencing

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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