Targeting SHP2 Phosphatase for Hematologic Malignancies in Noonan Syndrome

描述(申请人提供)：最近在发育障碍Noonan综合征和各种儿童白血病中发现了酪氨酸磷酸酶Ptpn11(Shp2)的种系和体细胞突变，如幼年性单核细胞白血病(JMML)、B细胞急性淋巴细胞白血病(B-ALL)和急性髓系白血病(AML)。这些突变导致Shp2催化活性的过度激活。我们实验室和其他实验室的研究表明，Ptpn11的一个单一疾病突变足以导致Noonan综合征和JMML样髓系增生性疾病，随后恶性进展为急性白血病，这表明Shp2的过度激活在这些疾病中起到了因果作用。Ptpn11和Noonan综合征的激活突变与儿童白血病之间的直接联系表明Shp2可能是预防/治疗Noonan综合征的恶性血液病的机制治疗的有用靶点。我们广泛的、长期的目标是确定Ptpn11激活突变导致Noonan综合征和儿童白血病的分子机制，并利用收集的信息开发这些疾病的新疗法。该项目的具体目的是验证Shp2抑制剂，包括我们实验室确定的一种临床使用的天然产物药物，用于抑制Ptpn11激活突变阳性白血病细胞。Ptpn11相关白血病的小鼠模型和JMML患者的骨髓细胞都将进行测试。预计这项工作将为使用Shp2抑制剂预防和治疗Noonan综合征的恶性血液病奠定理论基础。这些研究将极大地促进我们的实验室发现，即一种已知的临床使用的Shp2抑制剂药物，转化为临床试验。

DESCRIPTION (provided by applicant): Germline and somatic mutations in tyrosine phosphatase Ptpn11 (Shp2) have recently been identified in the developmental disorder Noonan syndrome and various childhood leukemias, such as juvenile myelomonocytic leukemia (JMML), B-cell acute lymphoblastic leukemia (B-ALL), and acute myeloid leukemia (AML). These mutations cause hyperactivation of Shp2 catalytic activity. Studies in our laboratory and others have demonstrated that a single disease mutation in Ptpn11 is sufficient to cause Noonan syndrome and JMML-like myeloid proliferative disease in mice followed by malignant progression to acute leukemias, suggesting that over activation of Shp2 plays a causal role in these diseases. Direct connection between activating mutations of Ptpn11 and Noonan syndrome and childhood leukemias indicates that Shp2 may be a useful target of mechanism-based therapeutics for preventing/treating hematologic malignancies in Noonan syndrome. Our broad, long-term objective is to determine the molecular mechanisms by which Ptpn11 activating mutations induce Noonan syndrome and childhood leukemias and to use the information gathered to develop novel therapeutics for these diseases. The specific aim of the proposed project is to validate the Shp2 inhibitors, including a clinically used natural product drug identified in our laboratory in suppressing Ptpn11 activating mutation-positive leukemia cells. Both a mouse model of Ptpn11-associated leukemias and JMML patient bone marrow cells will be tested. It is anticipated that this work will establish the rationale for using Shp2 inhibitors to prevent and treat hematologic malignancies in Noonan syndrome. These studies will greatly facilitate the translation of our laboratory finding, i.e., a known clinically used drug as a Shp2 inhibitor, to a clinical trial.