PPM1D in Clonal Hematopoiesis and Malignancies

PPM1D 在克隆造血和恶性肿瘤中的作用

• 批准号: 10655461
• 负责人: Lawrence A. Donehower
• 金额: $ 58.76万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10655461
• 关键词: Affect; Aging; Animals; Apoptosis; Architecture; Blood Cells; Bone Marrow; Bone Marrow Transplantation; C-terminal; Cells; Cellular Assay; Chemoresistance; Cisplatin; Clinical; Clonal Expansion; Clone Cells; Complex; DNA Damage; DNA Repair; DNA crosslink; Defect; Dependence; Development; Disease; Down-Regulation; Dysmyelopoietic Syndromes; Evolution; Exons; Exposure to; Failure; Feedback; Frequencies; Genes; Genetic Engineering; Genetic Transcription; Genetically Engineered Mouse; Genomics; Goals; Hematologic Neoplasms; Hematopoiesis; Hematopoietic; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Individual; Investigation; Leukemic Cell; Life; Malignant - descriptor; Malignant Neoplasms; Molecular Probes; Mus; Mutate; Mutation; Nonhomologous DNA End Joining; Oncogenes; Oncogenic; Organ; Outcome; PPM1D gene; Pathway interactions; Patients; Phosphoric Monoester Hydrolases; Preleukemia; Primary Neoplasm; Prior Chemotherapy; Production; Prognosis; Protein Dephosphorylation; Protein phosphatase; Proteins; Recurrence; Resistance; Risk; Role; Sampling; Secondary acute myeloid leukemia; Solid Neoplasm; Specimen; Stress; TP53 gene; Therapeutic; Therapeutic Agents; Variant; alpha-Thalassemia; cancer genome; cancer type; chemotherapeutic agent; chemotherapy; crosslink; design; driver mutation; experimental study; fitness; genome sequencing; genome wide screen; genotoxicity; improved; leukemia; leukemogenesis; member; mouse model; mutant; overexpression; peripheral blood; protective effect; protein expression; refractory cancer; repaired; response; targeted treatment; therapeutic evaluation; therapy design; transplant model; tumor; tumorigenesis

ABSTRACT Clonal hematopoiesis (CH) is a condition in which individual hematopoietic stem cells (HSCs) contribute disproportionately to peripheral blood production. Individuals with CH are at significantly greater risk of developing hematologic malignancies compared to those without CH. Analysis of CH-associated leukemias has recently revealed recurrent mutations in a number of cancer-associated genes, including PPM1D, which was previously not associated with leukemia development. In addition, PPM1D mutations have been observed in patients developing secondary leukemias after having received chemotherapy for prior non-hematopoietic solid tumors. PPM1D encodes the Wildtype p53-Induced Phosphatase 1 (WIP1), which is upregulated by p53 during DNA damage and acts homeostatically to dephosphorylate and downregulate DNA damage response proteins. PPM1D mutations are generally C-terminal truncating mutations that cause dramatic increases in WIP1 protein levels. It has been hypothesized that PPM1D mutations enhance fitness of hematopoietic stem and progenitor cells subjected to chemotherapeutic stress and may further contribute to malignant progression of HSC-derived cells in the context of other driver mutations. The precise mechanisms by which PPM1D mutations enhance hematopoietic cell fitness remain poorly understood. In this application we propose cellular, animal, and human patient studies to better understand how PPM1D mutations may drive clonal hematopoiesis and leukemogenesis with a long-term goal of testing therapeutic approaches that might target patients with malignancies that display such mutations. We propose four specific aims that include (1) the comparison of long term hematopoiesis and cancers in genetically engineered mice with a germline truncating mutation in Ppm1d; (2) the use of competitive HSC transplant experiments to analyze the fitness landscapes that impact the evolution and outcome of pre- leukemic hematopoiesis; (3) the use of genomic screens and cellular assays to identify pathways and elucidate functional mechanisms associated with PPM1D mutations in normal hematopoietic cells and leukemic cells; and (4) investigation of PPM1D-associated mutation signatures and clonal architecture of secondary leukemia and myelodysplastic syndrome cells arising in human patients exposed to previous chemotherapy for a primary tumor. These comprehensive studies on this newly discovered leukemia-associated oncogene may guide choice of therapeutic agents and elucidate mechanisms underlying the evolutionary selection of mutations that drive the progression from clonal dominance to malignancy.

摘要

项目成果

SRCAP mutations drive clonal hematopoiesis through epigenetic and DNA repair dysregulation.

• DOI: 10.1016/j.stem.2023.09.011
• 发表时间: 2023-10
• 期刊: Cell stem cell
• 影响因子: 23.9
• 作者: Chun-Wei Chen;Linda Zhang;Ravi Dutta;A. Niroula;Peter G. Miller;Christopher J. Gibson;A. Bick;Jaime M. Reyes;Yi-Tang Lee;A. Tovy;Tianpeng Gu;Sarah M. Waldvogel;Yi-Hung Chen;Bryan J. Venters;P. Estève;S. Pradhan;M. Keogh;Pradeep Natarajan;Koichi Takahashi;A. Sperling;M. Goodell

Untangling the Relationship Between Clonal Hematopoiesis and Ovarian Cancer Therapies.

阐明克隆造血与卵巢癌治疗之间的关系。

• DOI: 10.1093/jnci/djab234
• 发表时间: 2022
• 期刊: Journal of the National Cancer Institute
• 作者: Takahashi,Koichi