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Cell Stem Cell. 2018 Nov 1;23(5):700-713.e6. doi: 10.1016/j.stem.2018.10.004.

PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.

Author information

1
Translational Biology and Molecular Medicine Graduate Program and Medical Scientist Training Program, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
2
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77030, USA.
3
Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA.
4
Haematological Cancer Genetics, Wellcome Sanger Institute, Hinxton, Cambridge CB10 1SA, UK; Wellcome-MRC Stem Cell Institute, Cambridge Biomedical Campus, University of Cambridge, Cambridge CB2 0XY, UK.
5
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Center for Co-Clinical Trials, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
7
Department of Neurosurgery, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
8
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
9
Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Electronic address: ktakahashi@mdanderson.org.
10
Department of Pediatrics, Section of Hematology Oncology, Baylor College of Medicine, Houston, TX 77030, USA; Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: goodell@bcm.edu.

Abstract

Clonal hematopoiesis (CH), in which stem cell clones dominate blood production, becomes increasingly common with age and can presage malignancy development. The conditions that promote ascendancy of particular clones are unclear. We found that mutations in PPM1D (protein phosphatase Mn2+/Mg2+-dependent 1D), a DNA damage response regulator that is frequently mutated in CH, were present in one-fifth of patients with therapy-related acute myeloid leukemia or myelodysplastic syndrome and strongly correlated with cisplatin exposure. Cell lines with hyperactive PPM1D mutations expand to outcompete normal cells after exposure to cytotoxic DNA damaging agents including cisplatin, and this effect was predominantly mediated by increased resistance to apoptosis. Moreover, heterozygous mutant Ppm1d hematopoietic cells outcompeted their wild-type counterparts in vivo after exposure to cisplatin and doxorubicin, but not during recovery from bone marrow transplantation. These findings establish the clinical relevance of PPM1D mutations in CH and the importance of studying mutation-treatment interactions. VIDEO ABSTRACT.

KEYWORDS:

CHIP; DNA damage response; PPM1D; cisplatin; clonal hematopoiesis; doxorubicin; etoposide; t-AML; t-MDS; topoisomerase inhibitors

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