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

描述（由申请人提供）：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。人类混合谱系白血病（MLL）基因重排是急性白血病中最常见的异常之一，也是侵袭性（高风险）儿童、成人和拓扑异构酶相关病例的标志。了解MLL融合蛋白转化的机制将有助于开发针对这些患者的靶向治疗。MLL是Drosophila Trithorax （Trx）的同源物，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 （H3K4）甲基化介导。然而，随着MLL易位，负责这种酶活性的c端SET结构域丢失，并且截断。MLL在框架中融合到50多个易位伙伴中的一个。最常见的MLL易位伴侣是AF4、ENL、AF9和AF5q31，占MLL相关白血病的70%以上。这四个易位伙伴最近被证明在MPAC （MLL融合伙伴相关复合体）中直接相互作用，以及组蛋白3赖氨酸79甲基转移酶Dot1L， RNA聚合酶II c末端结构域激酶pTEFb， Polycomb组蛋白Pc3和Ring1b。本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。Specific Aim 1将讨论MPAC在转录激活和转化中的作用，而Specific Aim 2将评估MPAC亚基相互作用的调控。MPAC活性的研究将为MLL融合蛋白如何破坏正常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.