Synergistic role of signaling and epigenetics in leukemic transformation

项目摘要 遗传和功能数据已经证明了体细胞突变在信号传导效应器和信号转导系统中的重要性。 骨髓增生性肿瘤（MPN）和急性髓性白血病发病机制中的表观遗传修饰物 （AML）。然而，这两类白血病等位基因协同诱导白血病的机制是不确定的。 转化，以及信号通路和表观遗传调节因子中的协调突变如何影响 对靶向治疗的反应尚未完全阐明。在这里，我们建议调查如何突变， 信号传导效应子与表观遗传调节因子中的突变合作以诱导骨髓转化，并且 这些突变如何影响对靶向治疗的反应，包括治疗药物的开发。 阻力然后，我们将扩展我们的研究，以调查联合治疗方法是否可以 在骨髓增生性肿瘤（MPN）和急性髓性白血病模型中获得更高的疗效 （AML）。这项建议的长期目标是描述致癌疾病的新机制， 等位基因协同诱导白血病发生，并证明新的组合策略， 在临床背景下研究。我们将使用一种新颖的，基因上准确的 动物模型、鼠模型和患者样品中的表观基因组研究以及临床前治疗研究 旨在合理设计联合治疗策略。我们的研究有一个机械的重点，但 旨在将这些见解快速转化为临床背景。

Project Summary Genetic and functional data have demonstrated the importance of somatic mutations in signaling effectors and in epigenetic modifiers in the pathogenesis of myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). However, the mechanisms by which these two classes of leukemia disease alleles cooperate to induce transformation, and how coordinate mutations in signaling pathways and in epigenetic regulators affect the response to targeted therapy, has not been fully elucidated. Here we propose to investigate how mutations in signaling effectors cooperate with mutations in epigenetic regulators to induce myeloid transformation, and how these mutations influence the response to targeted therapies including the development of therapeutic resistance. We will then extend our studies to investigate whether combination therapeutic approaches can achieve increased efficacy in models of myeloproliferative neoplasms (MPN) and acute myeloid leukemia (AML). The long-term goals of this proposal are to characterize novel mechanisms by which oncogenic disease alleles cooperate to induce leukemogenesis, and to credential novel combination strategies that can be investigated in the clinical context. We will investigate this using a combination of novel, genetically accurate animal models, epigenomic studies in murine models and patient samples, and preclinical therapeutic studies aimed at rational design of combination therapeutic strategies. Our studies have a mechanistic focus, but are aimed to rapidly translate these insights to the clinical context.