Germline mutations of PTPN11 (SHP-2) in the stem cell microenvironment

干细胞微环境中 PTPN11 (SHP-2) 的种系突变

• 批准号: 9174534
• 负责人: CHENG-KUI QU
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-05 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174534
• 关键词: Acute leukemia; Address; Blood; Bone Marrow; Bone Marrow Cells; Cell surface; Cells; Childhood; Coculture Techniques; Data; Development; Disease; Embryonic Development; Evolution; Face; Failure; Germ-Line Mutation; Goals; Hematopoietic; Hematopoietic stem cells; Human; Juvenile Myelomonocytic Leukemia; Knock-in Mouse; Knowledge; Laboratories; Lead; Malignant Neoplasms; Mediating; Mental Retardation; Mesenchymal Stem Cells; Molecular; Mus; Mutate; Mutation; Myeloproliferative disease; Noonan Syndrome; PTPN11 gene; Pathogenesis; Patients; Plasma; Play; Protein Tyrosine Phosphatase; Proteins; Risk; Role; Signal Pathway; Signaling Molecule; Stem cell transplant; Stem cells; Stromal Cells; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transplantation; Treatment outcome; Work; base; cell type; congenital heart disorder; design; developmental disease; gain of function; improved; leukemia; leukemogenesis; mutant; nestin protein; new therapeutic target; novel; stem; stem cell niche

Project Summary Patients with Noonan syndrome (NS), a developmental disorder characterized by congenital heart disease, dysmorphic facial structures, short stature, and mental retardation, are at an increased risk of developing leukemias, especially juvenile myelomonocytic leukemia (JMML), a fatal childhood myeloproliferative neoplasm (MPN). The mechanisms underlying the leukemogenesis are not completely understood. Lack of such knowledge impedes the development of therapeutic interventions for effectively controlling leukemic progression in NS and for improving treatment outcomes in NS-associated leukemias. Germline activating mutations of PTPN11 (encoding SHP2), a protein tyrosine phosphatase that we previously demonstrated is required for embryogenesis and hematopoietic cell development, are associated with more than 50% of patients with NS. Studies from our laboratory and others have established a cell-intrinsic role of PTPN11 mutations in NS and associated leukemias. Intriguingly, our most recent studies suggest that PTPN11 mutations in the bone marrow (BM) microenvironment can also induce a profound myeloid malignancy. The objective of the current project is to determine the cellular and molecular mechanisms by which PTPN11 mutated microenvironmental cells impact resident hematopoietic stem cells. The central hypothesis of the proposal is that germline PTPN11 mutations in the BM microenvironment greatly promote the leukemic progression in NS and cause stem cell transplantation failure. We plan to test this hypothesis and accomplish the objective of this application by pursuing the following aims. 1). Identify the cellular components and protein factors that mediate the leukemogenic effects of PTPN11 mutations in the BM microenvironment. 2). Determine the molecular mechanisms by which PTPN11 mutations change the activities of microenvironmental cells. 3). validate the pathogenic effects of PTPN11 mutations in NS patient-derived BM microenvironmental cells. This project will not only greatly advance our understanding of the pathogenesis of NS-associated leukemias, but also provide a molecular basis for the rational design of new therapeutics targeting the detrimental microenvironment in NS patients, which may eventually lead to significant improvements in controlling leukemic progression in NS and in stem cell transplantation therapy for NS-associated leukemias.

项目总结