Journal
CELL STEM CELL
Volume 23, Issue 5, Pages 700-+Publisher
CELL PRESS
DOI: 10.1016/j.stem.2018.10.004
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Funding
- Center Prevention and Research Institute of Texas (CPRIT) [RP160451, R120501]
- NIH [DK092883, DK116428, S10RR024574, AI036211, P30 CA125123, P30 CA016672]
- Welch Foundation [G-0040]
- MDAnderson's MoonShot Program
- Baylor Research Advocates for Student Scientists
- BCM MSTP program
- Khalifa Physician Scientist Award
- Physician Scientist Program at MD Anderson
- Leukemia SPORE Career Enhancement Award
- Cancer Research UK Senior Cancer Research Fellowship [C22324/A23015]
- Kay Kendall Leukaemia Fund
- Bloodwise
- Sanger Institute [WT098051]
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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.
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