PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.
Hsu, Joanne I
De Braekeleer, Etienne
Heffernan, Timothy P
Kovacs, Jeffrey J
Marszalek, Joseph R
Futreal, P Andrew
Donehower, Lawrence A
Goodell, Margaret A
Cell Stem Cell
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Hsu, J. I., Dayaram, T., Tovy, A., De Braekeleer, E., Jeong, M., Wang, F., Zhang, J., et al. (2018). PPM1D Mutations Drive Clonal Hematopoiesis in Response to Cytotoxic Chemotherapy.. Cell Stem Cell, 23 (5), 700-713.e6. https://doi.org/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.
CHIP, DNA damage response, PPM1D, cisplatin, clonal hematopoiesis, doxorubicin, etoposide, t-AML, t-MDS, topoisomerase inhibitors
This work was supported by the Center Prevention and Research Institute of Texas (CPRIT) (RP160451 and R120501) and the NIH (DK092883, DK116428, S10RR024574, AI036211, P30 CA125123, and P30 CA016672). The Welch Foundation (G-0040), MD Anderson’s MoonShot Program, the Baylor Research Advocates for Student Scientists, and the BCM MSTP program also provided support. K.T. is supported by a Khalifa Physician Scientist Award, the Physician Scientist Program at MD Anderson, and a Leukemia SPORE Career Enhancement Award. G.V. is funded by a Cancer Research UK Senior Cancer Research Fellowship (C22324/A23015), the Kay Kendall Leukaemia Fund, Bloodwise, and core funding from the Sanger Institute (WT098051). We also thank the Samuel Waxman Cancer Research Foundation.
Cancer Research UK (23015)
External DOI: https://doi.org/10.1016/j.stem.2018.10.004
This record's URL: https://www.repository.cam.ac.uk/handle/1810/287508
Attribution 4.0 International
Licence URL: https://creativecommons.org/licenses/by/4.0/