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

PTPN11和NPM1突变在急性髓系白血病发展和治疗耐药中的作用

• 批准号: 10315877
• 负责人: Sydney Fobare
• 金额: $ 4.28万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2025-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10315877
• 关键词: Acute Myelocytic Leukemia; Address; Animals; Apoptotic; Biology; Cell Line; Cells; Chemoresistance; Clinical; Clinical Skills; Clonal Expansion; Communication; Comprehensive Cancer Center; Critical Thinking; Cytotoxic Chemotherapy; Data; Data Set; Development; Disease; Disease-Free Survival; Doctor of Philosophy; Experimental Designs; FDA approved; FLT3 gene; Foundations; Frequencies; Future; Genes; Genetic; Goals; Hematologic Neoplasms; Hematology; Human; Immune; Immunodeficient Mouse; Immunophenotyping; Immunosuppression; Impairment; Inferior; Interleukin-10; Knowledge; Laboratories; MAP Kinase Gene; MCL1 gene; Malignant - descriptor; Measures; Modeling; Mus; Mutate; Mutation; Myeloid Cells; Myeloid Progenitor Cells; NF-kappa B; NPM1 gene; New Agents; Ohio; Outcome; PTPN11 gene; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenocopy; Phenotype; Play; Pre-Clinical Model; Protein Tyrosine Phosphatase; Proteins; Proto-Oncogene Proteins c-akt; Relapse; Reporting; Research; Research Personnel; Research Proposals; Research Training; Resistance; Rest; Role; Signal Pathway; Signal Transduction; Supervision; T-Lymphocyte; Technical Expertise; Testing; Therapeutic; Time; Training; Transgenic Organisms; acute myeloid leukemia cell; adverse outcome; anticancer research; base; chemotherapy; cytokine; doctoral student; effective therapy; human disease; improved; leukemogenesis; mouse model; mutant; novel; novel therapeutics; nucleophosmin; overexpression; patient population; patient subsets; preclinical study; programs; resistance mechanism; response; skills; targeted treatment; therapy development; transcription factor; translational scientist; treatment strategy

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.

项目总结/摘要 急性髓系白血病（AML）是一种以髓系细胞克隆性扩增为特征的疾病， 分化尽管最近批准了AML的靶向治疗，但仍有很大一部分患者 其疾病进展或对治疗无反应。有一组病人已经证明 对靶向治疗（entospletinib、enasidenib、ivosidenib和venetoclax）的耐药有蛋白酪氨酸- 磷酸酶非受体11型（PTPN 11）突变。PTPN 11基因编码磷酸酶 Shp 2，调节包括RAS-MAPK通路在内的多种信号通路。PTPN 11突变 （PTPN 11+）通常与核磷蛋白（NPM 1）基因中的突变共同发生。我们的初步数据 表明PTPN 11和NPM 1突变的共同关联导致患者的预后较差， 接受了强化化疗有趣的是，我们已经看到PTPN 11 +/NPM 1+患者很少有 FLT 3-ITD，一种众所周知会恶化NPM 1 + AML结局的改变。因为PTPN 11突变 激活许多类似于FLT 3-ITD的下游信号通路，我们假设， PTPN 11突变为NPM 1 + AML可在临床上复制NPM 1 +/FLT 3-ITD AML的不良表型， 结果和治疗抵抗。因此，我们获得了一种新的转基因Ptpn 11 E76 K/Npm 1cA小鼠 模型来研究AML的发展和产生的免疫抑制表型。使用该模型， 我们将询问来自Ptpn 11 E76 K/Npm 1cA动物的扩增的髓样细胞是否可以在 免疫缺陷小鼠并赋予对化疗的抗性。此外，我们将使用修饰的AML细胞系 研究耐药机制，特别是信号通路，抗凋亡蛋白， 免疫抑制作用。所获得的知识将阐明AML中PTPN 11突变的生物学， 为开发对PTPN 11 + AML患者有效的疗法提供基础。 这项研究将由一名医学博士/博士生在两名主要翻译的监督下完成。 AML领域的研究人员。医学博士/博士项目在俄亥俄州已经建立，癌症研究 在综合癌症中心工作的人都非常强壮培训计划包括 批判性思维，科学知识，技术专长，临床技能的发展机会， 通信能力和严格的实验设计。成功完成研究计划 和培训计划将提供必要的技能，成为一个独立的研究领域， 血液学