MLL Family Histone Methyltransferases in Myeloid Leukemia

项目摘要 尽管在治疗某些类型的癌症方面取得了一些显着的进展，但突变的性质 急性髓细胞白血病（AML）的异质性使得这种癌症的治疗具有挑战性 成功地基因组数据已经提出了许多新的治疗靶点，但即使是成功的 分子抑制并不总是转化为有效的治疗，这证明了更广泛的 了解AML中改变的机制和途径。我们最近的研究表明， 内源性MLL 1和MLL 2组蛋白甲基转移酶参与的新途径 MLL融合癌蛋白驱动的白血病发生。在MLL-AF 9或MLL-AF 6驱动的AML中，我们 发现内源性MLL 2组蛋白甲基转移酶在维持 几个协调的途径，提高白血病生存和增殖。虽然MLL 1 它本身并不促进白血病的发生，它与MLL 2合作调节关键的 影响NFκB、整合素β3和IL-3信号传导的AML存活/增殖途径。鉴于 AML生存/增殖广泛依赖于所有这三种途径，我们建议 测试MLL 1和MLL 2在多种遗传学中的作用和下游途径。 定义的AML动物模型，以及人白血病细胞系和原始样品。 具体而言，我们的建议旨在1）确定MLL 1/MLL 2或两者的缺失是否影响AML 由多种遗传学定义的鼠AML模型驱动，2）鉴定MLL 1/MLL 2调节的 沿着人AML细胞中的通路以及MLL 2内的结构域， 这些途径，和3）定义转录组扰动，表观基因组状态，和 MLL 1和MLL 2在MLL-AF 9驱动的AML中均被敲除，并确定其机制 他们合作支持AML生存。这些实验将确定表观遗传 可能是特定于某些AML细胞遗传学亚型的脆弱性，也可能是广泛的脆弱性。 相关的

PROJECT SUMMARY Despite some remarkable advances in treating certain types of cancer, the nature of mutations and heterogeneity of acute myeloid leukemia (AML) have made this cancer challenging to treat successfully. Genomic data have suggested many new therapeutic targets, but even successful molecular inhibition does not always translate to effective therapy, justifying a broader understanding of mechanisms and pathways altered in AML. Our recent studies illuminated a novel pathway by which the endogenous MLL1 and MLL2 histone methyltransferases contribute to leukemogenesis driven by MLL fusion oncoproteins. In MLL-AF9 or MLL-AF6-driven AML, we found that the endogenous MLL2 histone methyltranferase played a major role in sustaining several coordinated pathways that enhance leukemia survival and proliferation. Although MLL1 did not contribute on its own to leukemogenesis, it collaborated with MLL2 in regulating critical AML survival/proliferation pathways affecting NFκB, integrin β3 and IL-3 signaling. Given the widespread reliance on all three of these pathways for AML survival/proliferation, we propose to test the role and downstream pathways regulated by MLL1 and MLL2 in a variety of genetically defined AML animal models, as well as human leukemia lines and primary samples. Specifically, our proposal aims to 1) determine whether loss of MLL1/MLL2 or both affects AML driven by a variety of genetically-defined murine AML models, 2) identify MLL1/MLL2 regulated pathways in human AML cells along with the domains within MLL2 that contribute regulating these pathways, and 3) define the transcriptome perturbations, epigenomic states, and effect of both Mll1 and Mll2 knockout in MLL-AF9-driven AML and determine the mechanism by which they collaborate to support AML survival. These experiments will identify epigenetic vulnerabilities that may be particular to certain cytogenetic subtypes of AML or may be broadly relevant.