@article{0f03e3ed07434c60b0d0e58ed2e8cf16,
title = "MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia",
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.",
keywords = "CXCR4, DNA damage, Fanconi anemia, MYC, bone marrow failure, genotoxic stress, hematopoietic stem cells, p53, physiological stress, single-cell RNA sequencing",
author = "Alfredo Rodr{\'i}guez and Kaiyang Zhang and Anniina F{\"a}rkkil{\"a} and Jessica Filiatrault and Chunyu Yang and Martha Vel{\'a}zquez and Elissa Furutani and Goldman, {Devorah C.} and {Garc{\'i}a de Teresa}, Benilde and Gilda Garza-May{\'e}n and Kelsey McQueen and Sambel, {Larissa A.} and Bertha Molina and Leda Torres and Marisol Gonz{\'a}lez and Eduardo Vadillo and Rosana Pelayo and Fleming, {William H.} and Markus Grompe and Akiko Shimamura and Sampsa Hautaniemi and Joel Greenberger and Sara Fr{\'i}as and Kalindi Parmar and D'Andrea, {Alan D.}",
note = "Funding Information: We thank the FA patients and their families and also the physicians, Ang{\'e}lica Monsiv{\'a}is and Gerardo L{\'o}pez, who referred the patients. This research was supported by grants from the National Institutes of Health ( R01HL052725 and P01HL048546 ), the Leukemia and Lymphoma Society ( 6237-13 ), and the Fanconi Anemia Research Fund (to A.D.D.); the European Union Horizon 2020 Research and Innovation Program ( 667403 for HERCULES); the Academy of Finland ; SEP-CONACYT ( 243102 ); PAPIIT ( IA202615 ); and FOSISS-CONACyT ( 233721 ). We thank Dr. Cailin E. Joyce for providing guidance regarding processing primary human bone marrow for scRNA-seq, Dr Patricia Flores and Dr. H{\'e}ctor Mayani for guidance in CFU analysis and Dr. Jun Qi for kindly providing the (+)-JQ1 and (−)-JQ1 enantiomers. Funding Information: We thank the FA patients and their families and also the physicians, Ang?lica Monsiv?is and Gerardo L?pez, who referred the patients. This research was supported by grants from the National Institutes of Health (R01HL052725 and P01HL048546), the Leukemia and Lymphoma Society (6237-13), and the Fanconi Anemia Research Fund (to A.D.D.); the European Union Horizon 2020 Research and Innovation Program (667403 for HERCULES); the Academy of Finland; SEP-CONACYT (243102); PAPIIT (IA202615); and FOSISS-CONACyT (233721). We thank Dr. Cailin E. Joyce for providing guidance regarding processing primary human bone marrow for scRNA-seq, Dr Patricia Flores and Dr. H?ctor Mayani for guidance in CFU analysis and Dr. Jun Qi for kindly providing the (+)-JQ1 and (?)-JQ1 enantiomers. A.R. K.P. and A.D.D. designed the experiments. K.Z. A.F. and S.H. developed bioinformatics tools and performed computational analysis and interpretation. A.R. performed experiments with help from J.F. C.Y. M.V. G.G.-M. K.M. L.A.S. B.M. L.T. M.G. and E.V. E.F. B.G.d.T. and A.S. provided samples and analyzed clinical data. R.P. M.G. S.F. and J.G. provided reagents and analyzed data. A.R. K.P. and A.D.D. analyzed and interpreted the data. A.R. K.P. and A.D.D. wrote the manuscript. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",
year = "2021",
month = jan,
day = "7",
doi = "10.1016/j.stem.2020.09.004",
language = "English (US)",
volume = "28",
pages = "33--47.e8",
journal = "Cell Stem Cell",
issn = "1934-5909",
publisher = "Cell Press",
number = "1",
}