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.

项目摘要 Noonan综合征（NS）的患者，一种以先天性心脏为特征的发育障碍 疾病，畸形面部结构，身材矮小和智力低下 发展白血病，尤其是少年脊髓细胞性白血病（JMML），致命的童年 骨髓增生性肿瘤（MPN）。白血病的基础机制并非完全 理解。缺乏这种知识阻碍了有效的治疗干预措施的发展 控制NS的白血病进展，并改善与NS相关的治疗结果 白血病。生殖线激活PTPN11的突变（编码SHP2），一种蛋白酪氨酸磷酸酶 我们以前证明的是胚胎发生和造血细胞发育所必需的 与超过50％的NS患者相关。我们实验室和其他人的研究 在NS和相关的白血病中，建立了PTPN11突变的细胞中性作用。有趣的是，我们的 最近的最新研究表明，骨髓（BM）微环境中的PTPN11突变可以 也诱发严重的髓样恶性肿瘤。当前项目的目的是确定 PTPN11突变的微环境细胞的细胞和分子机制影响驻留 造血干细胞。该提案的中心假设是种系PTPN11突变 BM微环境大大促进了NS的白血病进展并引起干细胞 移植失败。我们计划检验这一假设，并通过 追求以下目标。 1）。确定介导的细胞成分和蛋白质因子 BM微环境中PTPN11突变的白血病作用。 2）。确定分子 PTPN11突变改变微环境细胞活性的机制。 3）。证实 NS患者衍生的BM微环境细胞中PTPN11突变的致病作用。这 项目不仅会极大地提高我们对NS相关性白血病发病机理的理解， 但也为针对有害的新治疗剂的合理设计提供了分子基础 NS患者的微环境，最终可能导致控制的显着改善 NS和干细胞移植疗法的白血病进展。