Identifying the pathways that drive progression of the MPNs to AML

确定推动 MPN 进展为 AML 的途径

• 批准号: 10307030
• 负责人: John D Crispino
• 金额: $ 41.53万
• 依托单位: ST. JUDE CHILDREN'S RESEARCH HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-01 至 2021-09-21
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10307030
• 关键词: Alleles; Biogenesis; Biological Assay; Blood Coagulation Disorders; CRISPR screen; Cell Cycle; Cell model; Cells; Chronic Phase; Complication; Development; Disease; Disease Progression; Energy Metabolism; Event; Evolution; Extramedullary Hematopoiesis; Fatty Acids; Gene Expression; Gene Proteins; Genes; Genetic; Growth; Hematopoiesis; Hematopoietic; Hematopoietic stem cells; Hemorrhagic Thrombocythemia; Human; Impairment; In Vitro; JAK2 gene; Lead; Longevity; Mediating; Metabolism; Mitochondria; Mus; Mutate; Mutation; Myeloproliferative disease; Oncogenic; Oxidative Phosphorylation; Pathway interactions; Patients; Phenocopy; Phosphorylation; Polycythemia Vera; Primary Myelofibrosis; Proteins; Research; Role; STK11 gene; Signal Transduction; Splenomegaly; TP53 gene; Therapeutic Intervention; Translations; Work; cell growth; cytokine; disease-causing mutation; glucose uptake; improved; in vivo; inhibitor/antagonist; innovation; insight; leukemia; leukemic transformation; mouse model; mutant; new therapeutic target; novel therapeutics; overexpression; patient derived xenograft model; prevent; progenitor; self-renewal; sensor; tumor; tumor progression; tumorigenesis

PROJECT SUMMARY The myeloproliferative neoplasms (MPNs), which include polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are closely related clonal hematopoietic disorders that are characterized by extramedullary hematopoiesis, bleeding disorders, a shortened lifespan, and a propensity to evolve to AML. Currently there is no way to predict which patients will develop AML, and little is known about the genetic events that are associated with progression. The identification of drivers of leukemic transformation will improve our understanding of the disease and provide novel targets for therapeutic intervention. To define the pathways that drive AML progression, we performed a focused CRISPR/Cas9 screen to identify genes whose editing resulted in hematopoietic progenitor cell self-renewal of Jak2V617F cells but not wild-type progenitors. We identified STK11 and RPS6KA2 as two genes whose editing cooperates with the JAK2 mutant to promote transformation in vitro. Importantly we also found that STK11 and RPS6KA2 are downregulated and mutated in post-MPN AML, respectively, but not in chronic phase MPN. These results are highly innovative, provide significant insights into disease progression, and reveal two new pathways to development of AML. We hypothesize that alterations in STK11 induce AML by suppressing the activity of its substrates, including AMPK, and consequently altering cellular metabolism and protein translation, leading to increased expression of oncogenic proteins. Similarly, we hypothesize that genetic alterations in RPS6KA2 cause AML by impairing STK11 function and/or enhancing mTORC1 signaling and oncogenic protein translation. We propose to delve into the contributions of STK11 and RPS6KA2 to MPN progression by the following aims: 1) Investigate the mechanisms by which loss of STK11 induces progression of JAK2V617F mutant MPN to AML; and 2) Elucidate the contributions of alterations in RPS6KA2 to the progression of MPN to AML. Together these studies will yield important new insights into the genetic basis and mechanisms by which AML arises from the MPNs.

项目摘要 骨髓增生性肿瘤（MPN）包括真性红细胞增多症、原发性血小板增多症和 原发性骨髓纤维化是密切相关的克隆性造血疾病，其特征在于 髓外造血、出血性疾病、寿命缩短以及演变为AML的倾向。 目前还没有办法预测哪些患者会发展为AML，并且对遗传事件知之甚少 与疾病进展有关的识别白血病转化的驱动因素将改善我们的研究。 了解疾病，并为治疗干预提供新的靶点。来定义 为了推动AML进展，我们进行了一项集中的CRISPR/Cas9筛选，以确定其编辑导致 在造血祖细胞自我更新的Jak2V617F细胞，但不是野生型祖细胞。我们确定 STK11和RPS6KA2作为两个基因，其编辑与JAK2突变体协同促进转化 体外重要的是，我们还发现STK11和RPS6KA2在MPN后AML中下调和突变， 而在慢性期MPN中则没有。这些结果具有高度创新性，为以下方面提供了重要见解： 疾病进展，并揭示了AML发展的两条新途径。我们假设， STK11通过抑制其底物（包括AMPK）的活性并因此改变其活性来诱导AML。 细胞代谢和蛋白质翻译，导致致癌蛋白表达增加。同样我们 假设RPS6KA2中遗传改变通过损害STK11功能和/或增强STK11功能而引起AML， mTORC1信号传导和致癌蛋白翻译。我们建议深入研究STK11的贡献， RPS6KA2对MPN进展的影响，其目的如下：1）研究STK11缺失的机制， 诱导JAK2V617F突变型MPN向AML的进展;和2）阐明 RPS6KA2与MPN向AML进展的关系。这些研究将共同产生重要的新见解， AML由MPN引起的遗传基础和机制。