The role of PTPN11 and NPM1 mutations in acute myeloid leukemia development and therapy resistance

项目概要/摘要 急性髓系白血病 (AML) 是一种以骨髓细胞克隆性扩张为特征的疾病， 差异化。尽管新批准了针对 AML 的靶向疗法，但仍有很大一部分患者 其疾病进展或对治疗没有反应。一组患者已证明 对靶向治疗（entospletinib、enasidenib、ivosidenib 和 Venetoclax）的耐药性与蛋白质酪氨酸有关 磷酸酶非受体 11 型 (PTPN11) 突变。 PTPN11 基因编码磷酸酶 Shp2，调节多种信号通路，包括 RAS-MAPK 通路。 PTPN11突变 (PTPN11) 通常与核磷蛋白 (NPM1) 基因突变同时发生。我们的初步数据 表明 PTPN11 和 NPM1 突变的共同关联导致患者预后较差 接受强化化疗。有趣的是，我们发现 PTPN11 /NPM1 患者很少患有 FLT3-ITD，众所周知，这种改变会恶化 NPM1 AML 的结果。因为PTPN11突变 激活许多类似于FLT3-ITD的下游信号通路，我们假设添加 NPM1 AML 的 PTPN11 突变可以在不良反应方面临床表现 NPM1 /FLT3-ITD AML 结果和治疗抵抗。因此，我们产生了新型转基因 Ptpn11E76K/Npm1cA 小鼠 模型来研究 AML 的发展以及由此产生的免疫抑制表型。使用这个模型， 我们将探讨来自 Ptpn11E76K/Npm1cA 动物的扩增骨髓细胞是否可以在 免疫缺陷小鼠并赋予对化疗的抵抗力。此外，我们将使用改良的 AML 细胞系 研究耐药机制，特别是信号通路、抗凋亡蛋白和 发挥免疫抑制作用。所获得的知识将阐明 AML 和 PTPN11 突变的生物学原理 为开发对 PTPN11 AML 患者有效的疗法奠定了基础。 这项研究将由一名医学博士/博士生在两位领先的转化专家的监督下完成 AML 领域的研究人员。俄亥俄州立大学的医学博士/博士项目已经很完善，癌症研究 综合癌症中心的实力雄厚且异常强大。培训计划包含 发展批判性思维、科学知识、技术专长、临床技能、 沟通能力和严谨的实验设计。顺利完成研究计划 培训计划将提供成为该领域的独立研究员所需的技能 血液学。

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a disease characterized by clonal expansion of myeloid cells with blocked differentiation. Despite newly approved targeted therapies for AML, there is still a large subset of patients whose disease progresses or does not respond to treatment. One group of patients that have demonstrated resistance to targeted therapy (entospletinib, enasidenib, ivosidenib, and venetoclax) have protein tyrosine- phosphatase non-receptor type 11 (PTPN11) mutations. The PTPN11 gene encodes for the phosphatase Shp2, which regulates multiple signaling pathways including the RAS-MAPK pathway. PTPN11 mutations (PTPN11+) commonly co-occur with mutations in the nucleophosmin (NPM1) gene. Our preliminary data demonstrates that the co-association of PTPN11 and NPM1 mutations results in inferior outcomes for patients treated with intensive chemotherapy. Intriguingly, we have seen that PTPN11+/NPM1+ patients rarely have FLT3-ITD, an alteration that is well-known to worsen outcomes in NPM1+ AML. Because PTPN11 mutations activate many downstream signaling pathways similar to FLT3-ITD, we hypothesize that the addition of PTPN11 mutations to NPM1+ AML can clinically phenocopy NPM1+/FLT3-ITD AML in terms of adverse outcomes and therapy resistance. Therefore, we have generated a novel transgenic Ptpn11E76K/Npm1cA mouse model to study the development of AML and the resulting immunosuppressive phenotype. Using this model, we will interrogate whether expanded myeloid cells from Ptpn11E76K/Npm1cA animals can initiate AML in immunodeficient mice and confer resistance to chemotherapy. In addition, we will use modified AML cell lines to study the mechanism of resistance, particularly the roles signaling pathways, antiapoptotic proteins, and immunosuppression play. The knowledge gained will clarify the biology of PTPN11 mutations in AML and provide the foundation to develop therapies that will be effective in patients with PTPN11+ AML. This research will be completed by an MD/PhD student under the supervision of two leading translational researchers in the field of AML. The MD/PhD program is well established at Ohio State, and cancer research at the Comprehensive Cancer Center is robust and exceptionally strong. The training plan contains opportunities for the development of critical thinking, scientific knowledge, technical expertise, clinical skills, communication capabilities, and rigorous experimental design. Successful completion of the research proposal and training plan will provide the skills necessary to become an independent researcher in the field of hematology.