Identifying the pathways that drive progression of the MPNs to AML

确定推动 MPN 进展为 AML 的途径

基本信息

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
项目类别：
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

项目摘要

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.

项目概要骨髓增生性肿瘤 (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，其特征为髓外造血、出血性疾病、寿命缩短以及发展为 AML 的倾向。目前还没有办法预测哪些患者会患上 AML，而且对遗传事件知之甚少与进展相关的。白血病转化驱动因素的识别将改善我们的研究了解该疾病并为治疗干预提供新的目标。定义路径为了推动 AML 的进展，我们进行了重点 CRISPR/Cas9 筛选，以识别其编辑结果的基因影响 Jak2V617F 细胞的造血祖细胞自我更新，但不影响野生型祖细胞的自我更新。我们确定了 STK11和RPS6KA2这两个基因的编辑与JAK2突变体配合促进转化体外。重要的是，我们还发现 STK11 和 RPS6KA2 在 MPN 后 AML 中下调和突变，分别，但不在慢性期 MPN 中。这些结果具有高度创新性，提供了重要的见解疾病进展，并揭示了 AML 发展的两条新途径。我们假设改变 STK11 通过抑制其底物（包括 AMPK）的活性来诱导 AML，从而改变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 的基因改变通过损害 STK11 功能和/或增强 mTORC1 信号传导和致癌蛋白翻译。我们建议深入研究 STK11 和 RPS6KA2 通过以下目标进展为 MPN：1) 研究 STK11 丢失的机制诱导 JAK2V617F 突变体 MPN 进展为 AML； 2) 阐明改变的贡献 RPS6KA2 与 MPN 进展为 AML 的关系。这些研究将共同产生重要的新见解 AML 由 MPN 产生的遗传基础和机制。