ABERRANT SIGNALING IN ACUTE MYELOID LEUKEMIA

项目摘要 尽管付出了巨大的努力，但急性髓系白血病患者的长期治愈率还不够。 对化疗的抗药性很普遍，分子治疗的靶点才刚刚开始确定。 例如，编码转录因子和表观遗传调节因子的基因突变导致了大多数亚型 AML，但它们的分子病理生理学和药理可及性仍然不清楚。我们有 现在发现在AML中白血病基因的表达需要不同的分子相互作用 先锋转录因子MYB及其共激活因子CBP。值得注意的是，MYB的模拟肽抑制剂 转录共激活在大多数AML分子亚型中显示出强大的抗白血病活性 健康的细胞。这一提议的中心假设是，定义和阻断基因的分子机制 急性髓系白血病中异常的转录共激活将直接导致患者治疗的改善。目标1将定义 控制白血病MYB转录因子复合体异常激活的分子机制 致癌基因表达。目标2将寻求模拟多肽和靶向小的初步证据 分子抑制剂可用于体内拆除白血病转录复合体并开发出有效的 使用准确的遗传和患者来源的临床前小鼠模型的治疗策略。成功 该项目的完成有望产生基本的分子机制和有效的异常治疗方法。 AML中的转录因子和基因控制，从而为一个基本问题提供了基本的见解 人们对此仍然知之甚少。这对于认识和对待这一问题具有广泛而持久的意义 尤其是难治性白血病和一般的人类癌症。

Project Summary Despite intense efforts, the long-term cure rates of patients with acute myeloid leukemia are inadequate. Resistance to chemotherapy is prevalent, and targets for molecular therapies are only beginning to be defined. For example, mutation of genes encoding transcription factors and epigenetic regulators cause most subtypes of AML, but their molecular pathophysiology and pharmacologic accessibility remain poorly defined. We have now found that leukemogenic gene expression in AML requires distinct molecular interactions between the pioneer transcription factor MYB and its coactivator CBP. Remarkably, peptidomimetic inhibitors of MYB transcriptional coactivation exhibit potent anti-leukemia activity in most molecular subtypes of AML while sparing healthy cells. The central hypothesis of this proposal is that defining and blocking the molecular mechanisms of aberrant transcriptional coactivation in AML will lead directly to improved therapies for patients. Aim 1 will define the molecular mechanisms of aberrant activation of leukemic MYB transcription factor complexes that control oncogenic gene expression. Aim 2 will pursue the preliminary evidence that peptidomimetic and targeted small molecule inhibitors can be used to dismantle leukemic transcriptional complexes in vivo and develop effective therapeutic strategies using accurate genetic and patient-derived preclinical mouse models. Successful completion of this project is expected to yield essential molecular mechanisms and effective therapies of aberrant transcription factors and gene control in AML, thus providing essential insights into a fundamental problem that remains poorly understood. This should have broad and lasting significance for understanding and treating refractory leukemias in particular and human cancer generally.