Modeling Transformation: Myeloproliferative Neoplasms to Acute Myeloid Leukemia

模型转化：骨髓增生性肿瘤到急性髓系白血病

基本信息

批准号：
9207432
负责人：
Anna Sophia McKenney
金额：
$ 4.9万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-02-07 至 2018-02-06
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9207432
关键词：
Acute Myelocytic Leukemia Affect Alleles Antineoplastic Agents Biological Models Biology Blood Cells Blood specimen Bone Marrow Cells Cell Line Cells Chronic Phase Clinic Clinical Complication Data Disease Doctor of Philosophy Epigenetic Process Event Fright Genes Genetic Genomics Hematological Disease Human Investigation Isocitrate Dehydrogenase Janus kinase 2 Laboratories Learning MPL gene Malignant - descriptor Malignant Neoplasms Modeling Molecular Mutation Myeloproliferative disease Oncogenic Pathway interactions Patient Care Patients Play Population Process Proteins Publishing Route Sampling Scientist Secondary to Signal Transduction Supportive care System Testing Therapeutic Time Training drug efficacy effective therapy epigenomics human disease improved in vitro Model in vivo in vivo Model individual patient inhibitor/antagonist leukemia leukemogenesis mortality mouse model mutant novel novel therapeutics progenitor public health relevance response stem targeted treatment

项目摘要

DESCRIPTION (provided by applicant): Myeloproliferative neoplasms (MPN) are diseases that are characterized by overproduction of mature blood cells. These diseases are commonly characterized by somatic activating mutations in the Janus Kinase 2 (JAK2) pathway, including mutations in the JAK2 protein itself (JAK2V617F) or in the coexpressed thrombopoietin receptor MPLW515L/K. The most feared complication of MPN is the transformation to acute myeloid leukemia (AML) - patients with leukemic progression show a median survival of less than six months and ultimate mortality of 98%. Conventional anti-leukemic therapies have demonstrated little efficacy in patients with MPN who develop AML, and no therapy has been demonstrated beyond supportive care for these patients, indicating a powerful need for new models and improved approaches toward therapy of this disease. Because patients with MPN usually present to the clinic before they progress to leukemia, samples from patients taken before and after progression allow us to dissect the sequence of genomic and epigenomic events that are associated with leukemic transformation. In patient samples, mutations in the isocitrate dehydrogenase (IDH) and TET2 proteins, which are functionally related epigenetic effectors, have been associated with this transformation and significantly reduced leukemia-free survival. To date, no models of transformation from MPN to AML have been developed, and there are no published data investigating leukemic cooperativity between JAK2 and IDH mutations in vivo. In order to advance our understanding of the sequential events in leukemogenesis and improve therapeutic options for Post-MPN AML patients, we will explore this process through three approaches. Human samples of paired chronic phase and post-MPN AML samples will be examined using genetic and epigenetic studies to assess the impact of specific mutations on leukemic transformation. In vitro models, including cell lines and primary bone marrow cells, will be used to assess the epigenetic and signaling aberrations that occur at the time of transformation. Finally, a mouse model of leukemic transformation will be generated by expressing JAK2V617F and IDH mutations in a temporal and spatially controlled manner. This model will be subsequently used to assess the efficacy of JAK-STAT and IDH inhibitors, alone and in combination, to determine if targeting multiple oncogenic disease alleles results in increased drug efficacy. The approaches in this proposal provide platforms to train an aspiring MD-PhD scientist in translational biology using clinical genomics and biological models.

描述（由申请人提供）：骨髓增生性肿瘤（MPN）是疾病，其特征是成熟血细胞过量生产。这些疾病通常以Janus激酶2（JAK2）途径中的体细胞激活突变为特征，包括JAK2蛋白本身（JAK2V617F）或共表达血栓蛋白受体MPLW51515L/K中的突变。 MPN最担心的并发症是转化为急性髓样白血病（AML） - 白血病进展的患者的中位生存期少于六个月，最终死亡率为98％。常规的抗白血病疗法显示出在发展AML的MPN患者中几乎没有疗效，并且没有证明对这些患者的支持性护理超出支持，这表明对新模型的强大需求和改进的治疗方法对这种疾病进行了治疗。由于MPN的患者通常在诊所前往白血病之前出现在诊所中，因此从进展前后采集的患者的样本使我们能够剖析与白血病转化相关的基因组和表观基因组事件的序列。在患者样品中，与功能相关的表观遗传效应子的异位酸脱氢酶（IDH）和TET2蛋白的突变与这种转化有关，并显着降低了无白血病的生存率。迄今为止，尚未开发从MPN到AML的转换模型，并且尚无公开的数据调查Vivo中JAK2和IDH突变之间的白血病协作性。为了促进我们对白血病发生的顺序事件的理解，并改善了MPN AML患者的治疗选择，我们将通过三种方法探索这一过程。将使用遗传和表观遗传学研究检查配对慢性期和MPN AML样品的人类样品，以评估特定突变对白血病转化的影响。体外模型，包括细胞系和原代骨髓细胞，将用于评估转化时发生的表观遗传和信号畸变。最后，通过以时间和空间控制的方式表达JAK2V617F和IDH突变，将产生白血病转化的小鼠模型。随后将使用该模型来评估JAK-STAT和IDH抑制剂的功效，单独和组合，以确定靶向多种致癌疾病等位基因是否会增加药物疗效。该提案中的方法为使用临床基因组学和生物学模型培训有抱负的MD-PHD科学家提供了平台。