PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Video-Audio Media

MeSH terms

  • Aged
  • Animals
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Cisplatin / chemistry
  • Cisplatin / pharmacology*
  • Clone Cells / drug effects*
  • Doxorubicin / chemistry
  • Doxorubicin / pharmacology*
  • Drug Screening Assays, Antitumor
  • Female
  • HEK293 Cells
  • Hematopoiesis / drug effects*
  • Hematopoiesis / genetics
  • Humans
  • Leukemia, Myeloid, Acute / drug therapy*
  • Leukemia, Myeloid, Acute / metabolism
  • Leukemia, Myeloid, Acute / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred NOD
  • Middle Aged
  • Mutation*
  • Neoplasms, Experimental / drug therapy
  • Neoplasms, Experimental / metabolism
  • Neoplasms, Experimental / pathology
  • Protein Phosphatase 2C / genetics*
  • Protein Phosphatase 2C / metabolism


  • Antineoplastic Agents
  • Doxorubicin
  • PPM1D protein, human
  • Protein Phosphatase 2C
  • Cisplatin