PPM1D -truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells

Truncating mutations in the terminal exon of protein phosphatase Mg2 /Mn2 1D ( ) 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 mutations confer a chemoresist...

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Vydáno v:	Blood Ročník 132; číslo 11; s. 1095
Hlavní autoři:	Kahn, Josephine D, Miller, Peter G, Silver, Alexander J, Sellar, Rob S, Bhatt, Shruti, Gibson, Christopher, McConkey, Marie, Adams, Dylan, Mar, Brenton, Mertins, Philipp, Fereshetian, Shaunt, Krug, Karsten, Zhu, Haoling, Letai, Anthony, Carr, Steven A, Doench, John, Jaiswal, Siddhartha, Ebert, Benjamin L
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 13.09.2018
Témata:	Base Sequence Cell Line, Tumor CRISPR-Cas Systems Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics Enzyme Inhibitors - pharmacology Hematologic Neoplasms - drug therapy Hematologic Neoplasms - enzymology Hematologic Neoplasms - genetics Hematologic Neoplasms - pathology Hematopoietic Stem Cells - enzymology Hematopoietic Stem Cells - pathology Humans Myeloproliferative Disorders - drug therapy Myeloproliferative Disorders - enzymology Myeloproliferative Disorders - genetics Myeloproliferative Disorders - pathology Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Neoplastic Stem Cells - enzymology Neoplastic Stem Cells - pathology Protein Phosphatase 2C - antagonists & inhibitors Protein Phosphatase 2C - genetics Protein Phosphatase 2C - metabolism Sequence Deletion
ISSN:	1528-0020, 1528-0020
On-line přístup:	Zjistit podrobnosti o přístupu
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Shrnutí:	Truncating mutations in the terminal exon of protein phosphatase Mg2 /Mn2 1D ( ) 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 mutations confer a chemoresistance phenotype, resulting in the selective expansion of -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 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, -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 mutant cells. Finally, we show that the inhibitor preferentially kills -mutant cells, sensitizes the cells to chemotherapy, and reverses the chemoresistance phenotype. These results provide an explanation for the enrichment of truncating 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 -mutant cells and the treatment of -mutant disease.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1528-0020 1528-0020
DOI:	10.1182/blood-2018-05-850339