PPM1D-truncating mutations confer resistance to chemotherapy and sensitivity to PPM1D inhibition in hematopoietic cells
Open accessAbstract
Key Points Truncating PPM1D mutations confer chemotherapy resistance, leading to the selective expansion of PPM1D-mutant cells in vitro and in vivo. PPM1D inhibitor treatment reverses the chemotherapy-resistance phenotype and selectively kills PPM1D-mutant cells.
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Ppm1d loss confers an advantage only in the context of the selective environment of cytotoxic chemotherapy or radiation, but not in steady-state post-transplant conditions.
“Ppm1d loss confers an advantage only in the context of the selective environment of cytotoxic chemotherapy or radiation, but not in steady-state post-transplant conditions [53,54].”
From Clonal hematopoiesis and inflammation – the perpetual cycle (2023) · cites this paper as [53]
HSCs from mice with mutations in both Tp53 and Ppm1d are able to enter cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.
“HSCs from mice with mutations in both Tp53 42 and Ppm1d, a gene encoding a regulator of p53 and other members of the DNA damage response pathway, 43,44 are able to enter cell cycle despite the presence of DNA damage, leading to a stem cell advantage in the setting of cytotoxic drugs.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [43]
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Clonal Hematopoiesis of Indeterminate Potential From a Heart Failure Specialist's Point of View
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Criteria for Diagnosis and Molecular Monitoring of NPM1-Mutated AML
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A Broad Overview of Signaling in Ph-Negative Classic Myeloproliferative Neoplasms
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Clonal hematopoiesis in older patients with breast cancer receiving chemotherapy
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Investigation of cancer drug resistance mechanisms by phosphoproteomics
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Aging and Clonal Behavior of Hematopoietic Stem Cells
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Clonal Hematopoiesis and risk of Acute Myeloid Leukemia
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Clonal Hematopoiesis: Updates and Implications at the Solid Tumor-Immune Interface
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Inflammageing and clonal haematopoiesis interplay and their impact on human disease
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Fate of Hematopoiesis During Aging. What Do We Really Know, and What are its Implications?
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Genetic Background of Polycythemia Vera
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Ppm1d truncating mutations promote the development of genotoxic stress-induced AML
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Implications of Clonal Hematopoiesis for Precision Oncology
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Clonal Hematopoiesis and Mutations of Myeloproliferative Neoplasms
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Murine models of clonal haematopoiesis to assess mechanisms of cardiovascular disease
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Distinct landscape and clinical implications of therapy-related clonal hematopoiesis
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Clonal Hematopoiesis and therapy related MDS/AML
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PPM1D in Solid and Hematologic Malignancies: Friend and Foe?
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p53 involvement in clonal hematopoiesis of indeterminate potential
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PPM1D Is a Therapeutic Target in Childhood Neural Tumors
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- Authors
- Kahn, J. D., Miller, P. G., Silver, A. J., Sellar, R. S., Bhatt, S., Gibson, C., McConkey, M., Adams, D., Mar, B., Mertins, P., Fereshetian, S., Krug, K., Zhu, H., Letai, A., Carr, S. A., Doench, J., Jaiswal, S., & Ebert, B. L.
- Affiliations
- Broad Institute (US)
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Corresponding author
- Jaiswal, Siddhartha
- Ebert, Benjamin L.
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2018-09-13
- Volume
- 132
- Issue
- 11
- Pages
- 1095-1105
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC6137556
- OpenAlex
- W2810683705
- Cited by
- 225
- References
- 30
- Citations by year
- 2026: 16 · 2025: 24 · 2024: 26 · 2023: 33 · 2022: 38 · 2021: 27 · 2020: 31 · 2019: 24 · 2018: 5
- FWCI
- 7.73
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Blood (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Heart, Lung, and Blood Institute (R01HL082945, T32HL116324, T32HL066987)
- National Cancer Institute (P01CA108631, P50CA206963, P01CA066996)
- National Institute of General Medical Sciences (R01GM038627)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Chronic Myeloid Leukemia Treatments
- Keywords
- PPM1D, truncating mutations, chemoresistance, hematopoietic cells, hematologic malignancies, phosphatase
- MeSH terms
- Protein Phosphatase 2C, Base Sequence, Enzyme Inhibitors, Hematopoietic Stem Cells, Humans, Myeloproliferative Disorders, Neoplasm Proteins, Neoplastic Stem Cells, Sequence Deletion, Drug Resistance, Neoplasm, Hematologic Neoplasms, Cell Line, Tumor, CRISPR-Cas Systems
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