Targeted therapy for 11q23 acute leukemias.

描述（由申请人提供）：尽管白血病的治疗取得了相当大的进展，特别是在儿童中，但白血病的几个子集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的特征在于涉及位于染色体11 q23的MLL基因的染色体易位。 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以下假设：靶向在这些类型的白血病中独特表达的基因产物的合成肽将选择性地抑制它们的生长。 本文提供的研究结果表明，MLL融合伴侣AF 9的羧基末端与另一个MLL融合伴侣AF 4的小结构域相互作用。 AF 9和AF 4的这些部分都存在于白血病相关的MLL融合蛋白中，表明AF 9和AF 4能够以其天然形式和/或作为MLL融合蛋白相互作用。 MLL-AF 4的物理相互作用 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 已经开发了一种小的合成肽，其在体外破坏AF 4和AF 9的相互作用。此外，该肽特异性抑制t（4;11）白血病细胞系的增殖。 对人类健康很重要的是，这种肽-或衍生化合物-可以提供一种治疗婴儿白血病或其他t（4;11）重排白血病患者的独特方法。该研究项目的更具体的目标是测试该肽结合AF 9并破坏其与t（4;11）白血病细胞中MLL-AF 4的相互作用的假设。 我们预测该肽也结合缺乏t（4;11）重排的白血病细胞中的AF 9，但数据表明，破坏天然蛋白质复合物对这些细胞几乎没有影响。最后，我们将对AF 4-AF 9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，为合理设计阻断AF 4-AF 9结合的肽提供基础。 最终，这些研究可能导致开发肽或相关化合物，用于有效治疗众所周知的困难的人类疾病，包括婴儿白血病和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.