PPM1D -truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells.
Autor: | Kahn JD; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Netherlands Cancer Institute, Amsterdam, The Netherlands., Miller PG; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Silver AJ; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Sellar RS; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; UCL Cancer Institute, University College London, London, United Kingdom., Bhatt S; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Gibson C; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., McConkey M; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Adams D; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA., Mar B; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Mertins P; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA.; Proteomics Platform, Max Delbruck Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany.; Berlin Institute of Health, Berlin, Germany., Fereshetian S; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA., Krug K; Proteomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA., Zhu H; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Letai A; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA., Carr SA; Broad Institute of MIT and Harvard, Cambridge, MA., Doench J; Genetic Perturbation Platform, Broad Institute of MIT and Harvard, Cambridge, MA; and., Jaiswal S; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Pathology, School of Medicine, Stanford University, Stanford, CA., Ebert BL; Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.; Broad Institute of MIT and Harvard, Cambridge, MA.; Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA. |
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Jazyk: | angličtina |
Zdroj: | Blood [Blood] 2018 Sep 13; Vol. 132 (11), pp. 1095-1105. Date of Electronic Publication: 2018 Jun 28. |
DOI: | 10.1182/blood-2018-05-850339 |
Abstrakt: | Truncating mutations in the terminal exon of protein phosphatase Mg2 + /Mn2 + 1D ( PPM1D ) have been identified in clonal hematopoiesis and myeloid neoplasms, with a striking enrichment in patients previously exposed to chemotherapy. In this study, we demonstrate that truncating PPM1D mutations confer a chemoresistance phenotype, resulting in the selective expansion of PPM1D -mutant hematopoietic cells in the presence of chemotherapy in vitro and in vivo. Clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein-9 nuclease mutational profiling of PPM1D in the presence of chemotherapy selected for the same exon 6 mutations identified in patient samples. These exon 6 mutations encode for a truncated protein that displays elevated expression and activity due to loss of a C-terminal degradation domain. Global phosphoproteomic profiling revealed altered phosphorylation of target proteins in the presence of the mutation, highlighting multiple pathways including the DNA damage response (DDR). In the presence of chemotherapy, PPM1D -mutant cells have an abrogated DDR resulting in altered cell cycle progression, decreased apoptosis, and reduced mitochondrial priming. We demonstrate that treatment with an allosteric, small molecule inhibitor of PPM1D reverts the phosphoproteomic, DDR, apoptotic, and mitochondrial priming changes observed in PPM1D- mutant cells. Finally, we show that the inhibitor preferentially kills PPM1D -mutant cells, sensitizes the cells to chemotherapy, and reverses the chemoresistance phenotype. These results provide an explanation for the enrichment of truncating PPM1D mutations in the blood of patients exposed to chemotherapy and in therapy-related myeloid neoplasms, and demonstrate that PPM1D can be a targeted in the prevention of clonal expansion of PPM1D -mutant cells and the treatment of PPM1D -mutant disease. (© 2018 by The American Society of Hematology.) |
Databáze: | MEDLINE |
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