PPM1D modulates hematopoietic cell fitness and response to DNA damage and is a therapeutic target in myeloid malignancy.

Autor:	Miller PG; Center for Cancer Research, Massachusetts General Hospital, Boston, MA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA., Sperling AS; Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Boston, MA., Mayerhofer C; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Harvard Stem Cell Institute, Harvard University, Cambridge, MA., McConkey ME; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Ellegast JM; Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Da Silva C; Center for Cancer Research, Massachusetts General Hospital, Boston, MA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Medical School, Boston, MA., Cohen DN; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Wang C; National University of Singapore, Singapore., Sharda A; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland., Yan N; Center for Cancer Research, Massachusetts General Hospital, Boston, MA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Medical School, Boston, MA., Saha S; Center for Cancer Research, Massachusetts General Hospital, Boston, MA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Medical School, Boston, MA., Schluter C; Center for Cancer Research, Massachusetts General Hospital, Boston, MA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Medical School, Boston, MA., Schechter I; Center for Cancer Research, Massachusetts General Hospital, Boston, MA.; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Medical School, Boston, MA., Słabicki M; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Sandoval B; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Kahn J; Department of Medicine, Brigham and Women's Hospital, Boston, MA., Boettcher S; Department of Medical Oncology and Hematology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.; Comprehensive Cancer Center Zurich, Zurich, Switzerland., Gibson CJ; Harvard Medical School, Boston, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Scadden DT; Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA.; Harvard Medical School, Boston, MA.; Harvard Stem Cell Institute, Harvard University, Cambridge, MA.; Department of Stem Cell and Regenerative Biology, Harvard University, Boston, MA.; Ludwig Center at Harvard, Boston, MA., Stegmaier K; Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Bhatt S; National University of Singapore, Singapore., Lindsley RC; Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA., Ebert BL; Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.; Howard Hughes Medical Institute, Bethesda, MD.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2023 Dec 14; Vol. 142 (24), pp. 2079-2091.
DOI:	10.1182/blood.2023020331
Abstrakt:	PPM1D encodes a phosphatase that is recurrently activated across cancer, most notably in therapy-related myeloid neoplasms. However, the function of PPM1D in hematopoiesis and its contribution to tumor cell growth remain incompletely understood. Using conditional mouse models, we uncover a central role for Ppm1d in hematopoiesis and validate its potential as a therapeutic target. We find that Ppm1d regulates the competitive fitness and self-renewal of hematopoietic stem cells (HSCs) with and without exogenous genotoxic stresses. We also show that although Ppm1d activation confers cellular resistance to cytotoxic therapy, it does so to a lesser degree than p53 loss, informing the clonal competition phenotypes often observed in human studies. Notably, loss of Ppm1d sensitizes leukemias to cytotoxic therapies in vitro and in vivo, even in the absence of a Ppm1d mutation. Vulnerability to PPM1D inhibition is observed across many cancer types and dependent on p53 activity. Importantly, organism-wide loss of Ppm1d in adult mice is well tolerated, supporting the tolerability of pharmacologically targeting PPM1D. Our data link PPM1D gain-of-function mutations to the clonal expansion of HSCs, inform human genetic observations, and support the therapeutic targeting of PPM1D in cancer. (© 2023 by The American Society of Hematology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)
Databáze:	MEDLINE
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