The role of MLL fusion Partner Associated Complex (MPAC) in leukemia

描述（申请人提供）：美国每年约有44，000人被诊断患有急性白血病，22，000人死于该疾病。 人混合谱系白血病（MLL）基因的重排是急性白血病中最常见的异常之一，并且是侵袭性（高风险）儿科、成人和拓扑异构酶II相关病例的标志。 了解MLL融合蛋白的转化机制将有助于为这些患者开发靶向治疗。 MLL是三胸果蝇（Drosophila Trithorax，Trx）的同源物，其参与靶基因的转录激活。 这种活性部分通过组蛋白3赖氨酸4（H3 K4）甲基化介导。 然而，随着MLL易位，负责这种酶活性的C-末端SET结构域丢失，并且被截短。 MLL与50多个易位伴侣之一在读框内融合。 最常见的MLL易位伴侣是AF 4，ENL，AF 9和AF 5 q31，占MLL相关白血病的70%以上。 这四个易位伴侣最近被证明在称为MPAC（MLL融合伴侣相关复合物）的复合物中直接相互作用，沿着有组蛋白3赖氨酸79甲基转移酶Dot 1 L、RNA聚合酶II C-末端结构域激酶pTEFb和Polycomb组蛋白Pc 3和Ring 1b。 这项提案将研究这些不同的蛋白质如何相互作用，以促进白血病的发生。 具体目标1将解决MPAC在转录激活和转化中的作用，具体目标2将评估MPAC亚基相互作用的调节。 对MPAC活性的研究将为了解MLL融合蛋白如何破坏正常的转录机制以及如何靶向治疗提供有价值的见解。

DESCRIPTION (provided by applicant): Around 44,000 people in the United States are diagnosed with acute leukemia each year and 22,000 people die from the disease. Rearrangements of the human Mixed Lineage Leukemia (MLL) gene are one of the most common abnormalities in acute leukemia and are a hallmark for aggressive (high-risk) pediatric, adult and topoisomerase ll-associated cases. Understanding the mechanisms of transformation by MLL fusion proteins will be useful in developing targeted therapy for these patients. MLL is a homologue of Drosophila Trithorax (Trx), which is involved in the transcriptional activation of the target genes. This activity is mediated in part through histone 3 lysine 4 (H3K4) methylation. However, with MLL translocation, the C-terminal SET domain responsible for this enzymatic activity is lost, and the truncated. MLL is fused in frame to one of more than fifty translocation partners. The most common MLL translocation partners are AF4, ENL, AF9 and AF5q31, which accounts for more than 70% of MLL-associated leukemias. These four translocation partners have recently been shown to directly interact in a complex called MPAC (MLL fusion Partner Associated Complex), along with histone 3 lysine 79 methyltransferase Dot1L, RNA polymerase II C-terminal domain kinase pTEFb, and Polycomb group proteins Pc3 and Ring1b. This proposal will study how these diverse proteins interact with each other to promote leukemogenesis. Specific Aim 1 will address the role of MPAC in transcriptional activation and transformation, and Specific Aim 2 will assess the regulation of MPAC subunit interaction. Study of the MPAC activity will provide valuable insights into how normal transcriptional mechanisms are disrupted by MLL fusion proteins and how these may be targeted therapeutically.