PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.

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, hetero

SUBMITTER: Hsu JI 

PROVIDER: S-EPMC6224657 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature