Targeted therapy for 11q23 acute leukemias.

尽管在白血病的治疗方面取得了相当大的进展，特别是在儿童中， 白血病仍然对治疗具有高度抗性。两种类型的耐药疾病，婴儿急性白血病和 表鬼臼毒素诱导的继发性白血病以染色体易位为特征， MLL基因定位于染色体11 q23。在这两种情况下，相互易位导致 嵌合MLL融合基因的表达。本提案的总体目标是检验假设 一种针对这些类型白血病中独特表达的基因产物的合成肽， 选择性地抑制它们的生长。本文提供的研究结果表明MLL的羧基末端 融合伴侣AF 9与另一MLL融合伴侣AF 4的小结构域相互作用。这两部分 AF 9和AF 4存在于白血病相关的MLL融合蛋白中，表明AF 9和AF 4是白血病相关的MLL融合蛋白。 能够以其天然形式和/或作为MLL融合蛋白相互作用。MLL的物理相互作用- AF 4和AF 9可能在t（4;11）（q21 ;q23）易位细胞的白血病发生中起重要作用 婴儿白血病的特征已经开发出一种小的合成肽， olAF 4和AF 9的体外表达。此外，所述肽特异性地抑制FT（4;11）白血病细胞的增殖 线对人类健康很重要的是，这种肽-或衍生化合物-可以提供一种独特的手段， 治疗患有婴儿白血病或其他具有T（4;11）重排的白血病的患者。越具体 该研究项目的目标是检验这种肽与AF 9结合并破坏其相互作用的假设 MLL-AF 4在t（4;11）白血病细胞中的表达。我们预测，这种肽也可以结合白血病细胞中的AF 9， 缺乏t（4;11）重排，但数据表明，天然蛋白质复合物的破坏对 这些细胞。最后，我们将对AF 4-AF 9蛋白相互作用进行广泛的突变分析。 结构域，以确定介导结合的关键接触点，为合理设计 肽以阻断AF 4-AF 9结合。最终，这些研究可能会导致肽的开发， 用于有效治疗众所周知的人类疑难疾病的相关化合物 白血病和治疗相关的继发性白血病。

Despite considerable progress in the treatment of leukemia, particularly in children, several subsets of leukemia remain highly resistant to treatment. Two types of resistant disease, acute leukemia in infants and epipodophyllotoxin-indueed secondary leukemia are characterized by chromosomal transloeations involving the MLL gene located at chromosome 1lq23. In both eases, the reciprocal translocation results in the expression of a chimeric MLL fusion gene. The overall objective of this proposal is to test the hypothesis that a synthetic peptide that targets gene products uniquely expressed in these types of leukemia will selectively inhibit their growth. Findings presented herein indicate that the carboxy-terminus of the MLL fusion partner AF9 interacts with a small domain of another MLL fusion partner AF4. These portions of both AF9 and AF4 are present in leukemia-associated MLL fusion proteins suggesting that AF9 and AF4 are capable of interacting in their native form and/or as MLL fusion proteins. The physical interaction of MLL- AF4 with AF9 may be important in leukemogenesis in cells with t(4;11)(q21 ;q23) translocations characteristic of infant leukemia. A small synthetic peptide has been developed that disrupts the interaction olAF4 and AF9 in vitro. Furthermore, the peptide specifically inhibits proliferation oft(4;11) leukemia cell lines. Important to human health, this peptide- or derivative compounds- could provide a unique means of treating patients with infant leukemia or other leukemias with t(4;11) rearrangements. The more specific goals of this research project are to test the hypothesis that the peptide binds AF9 and disrupts its interaction with MLL-AF4 in t(4;11) leukemia cells. We predict that the peptide also binds AF9 in leukemia cells that lack t(4;11) rearrangements but data suggests that disruption of a native protein complex has tittle effect on these cells. Finally, we will perform an extensive mutational analysis of the AF4-AF9 protein interaction domains to determine the critical contact points that mediate binding to provide a basis for rational design of peptides to block AF4-AF9 binding. Ultimately, these studies may lead to the development ofpeptides or related compounds for the effective treatment of notoriously difficult human diseases including infant leukemia and treatment-related secondary leukemia.