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

项目摘要 努南综合征(NS)患者，这是一种以先天性心脏为特征的发育障碍 疾病、面部结构畸形、身材矮小和智力低下，都有更高的风险。 发展中的白血病，特别是幼年粒单核细胞白血病(JMML)，一个致命的童年 骨髓增生性肿瘤(MPN)。白血病发生的潜在机制并不完全 明白了。缺乏这种知识阻碍了有效治疗干预措施的发展 控制NS中的白血病进展并改善NS相关患者的治疗结果 白血病。蛋白质酪氨酸磷酸酶PTPN11(编码SHP2)的种系激活突变 我们之前证明的胚胎发育和造血细胞发育所需的 与超过50%的NS患者有关。我们实验室和其他实验室的研究已经 确定了PTPN11突变在NS和相关白血病中的细胞内在作用。有趣的是，我们的 最近的研究表明，骨髓(BM)微环境中的PTPN11突变可以 也会诱发一种严重的髓系恶性肿瘤。当前项目的目标是确定 PTPN11突变的微环境细胞影响居民的细胞和分子机制 造血干细胞。这项提议的中心假设是，在 骨髓微环境极大地促进了NS的白血病进展，并导致干细胞 移植失败。我们计划测试这一假设，并通过以下方式实现此应用程序的目标 追求以下目标。1)。确定细胞成分和蛋白质因子，以调节 骨髓微环境中PTPN11突变的白血病效应。2)。确定分子 PTPN11突变改变微环境细胞活性的机制。3)。验证 PTPN11突变对NS患者骨髓微环境细胞的致病作用。这 该项目不仅将极大地促进我们对NS相关性白血病发病机制的了解， 同时也为合理设计新的治疗方法提供了分子基础 NS患者的微环境，这最终可能导致控制的显著改善 NS中的白血病进展和NS相关性白血病的干细胞移植治疗。

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.