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

项目摘要/摘要 急性髓系白血病(AML)是一种以髓系细胞克隆性扩张为特征的疾病 差异化。尽管新近批准了针对AML的靶向治疗，但仍有一大部分患者 其疾病进展或对治疗无效。一组患者已经证明了 对靶向治疗(entospletinib、enasidenib、ivosidenib和ventoclax)的耐药性有蛋白酪氨酸- 磷酸酶非受体11型(PTPN11)突变。PTPN11基因编码磷酸酶 Shp2，它调节包括Ras-MAPK通路在内的多个信号通路。PTPN11突变 (PTPN11)通常与核磷蛋白(NPM1)基因突变共存。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患者很少有 众所周知，Flt3-ITD的改变会恶化NPM1 AML的预后。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 PTPN11突变的NPM1 AML可在临床表现为NPM1/Flt3-ITD AML 结果和治疗抵抗。因此，我们获得了一种新型的转基因小鼠Ptpn11E76K/Npm1cA 模型研究急性髓系白血病的发展和由此产生的免疫抑制表型。使用这个模型， 我们将询问来自Ptpn11E76K/Npm1cA动物的扩增的髓系细胞是否可以在 免疫缺陷的小鼠，并对化疗产生抗药性。此外，我们还将使用改良的AML细胞系 研究抗病机制，特别是信号转导途径、抗凋亡蛋白和 免疫抑制发挥作用。所获得的知识将澄清AML和AML中PTPN11突变的生物学 为开发对PTPN11 AML患者有效的治疗方法提供基础。 这项研究将由一名医学博士/博士生在两位领先的翻译指导下完成 急性髓系白血病领域的研究人员。医学博士项目在俄亥俄州立大学已经很好地建立了，癌症研究 在综合癌症中心是强大的和异常强大的。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、 沟通能力强，实验设计严谨。顺利完成研究计划 和培训计划将提供必要的技能，以成为一名独立的研究人员在 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.