Targeted therapy for 11q23 acute leukemias.

描述(申请人提供)：尽管白血病的治疗，特别是儿童白血病的治疗取得了长足的进步，但白血病的几个亚型仍然对治疗具有高度的耐药性。两种耐药疾病，婴儿急性白血病和表鬼臼毒素诱导的继发性白血病的特点是染色体易位涉及位于染色体11q23的MLL基因。在这两种情况下，相互易位导致嵌合MLL融合基因的表达。这项建议的总体目标是测试一种假设，即针对在这些类型的白血病中唯一表达的基因产物的合成肽将选择性地抑制它们的生长。本文的研究结果表明，MLL融合伙伴AF9的羧基末端与另一个MLL融合伙伴AF4的一个小结构域相互作用。AF9和AF4的这两个部分都存在于白血病相关的MLL融合蛋白中，这表明AF9和AF4能够以天然形式和/或作为MLL融合蛋白相互作用。MLL-AF4的物理相互作用 AF9可能在t(4；11)(q21；q23)易位细胞的白血病发生中起重要作用 具有婴儿白血病的特征。一种能在体外干扰AF4和AF9相互作用的合成小肽已经被开发出来。此外，该多肽还能特异性地抑制t(4；11)白血病细胞系的增殖。这种多肽或衍生化合物对人类健康很重要，可以提供一种独特的方法来治疗t(4；11)重排的婴儿白血病或其他白血病患者。这项研究项目更具体的目标是在t(4；11)白血病细胞中测试该肽与AF9结合并破坏其与MLL-AF4相互作用的假设。我们预测，在缺乏t(4；11)重排的白血病细胞中，该肽也与AF9结合，但数据表明，天然蛋白复合体的破坏对这些细胞几乎没有影响。最后，我们将对AF4-AF9蛋白相互作用结构域进行广泛的突变分析，以确定介导结合的关键接触点，为合理设计多肽来阻断AF4-AF9结合提供依据。最终，这些研究可能导致多肽或相关化合物的开发，用于有效治疗臭名昭著的疑难人类疾病，包括婴儿白血病和与治疗相关的继发性白血病。

DESCRIPTION (provided by applicant): 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-induced secondary leukemia are characterized by chromosomal translocations involving the MLL gene located at chromosome 11q23. In both cases, 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 of AF4 and AF9 in vitro. Furthermore, the peptide specifically inhibits proliferation of t(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 little 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 of peptides or related compounds for the effective treatment of notoriously difficult human diseases including infant leukemia and treatment-related secondary leukemia.