Targeted therapy for 11q23 acute leukemias.

11q23急性白血病的靶向治疗。

• 批准号: 6778991
• 负责人: Charles Stanley Hemenway
• 金额: $ 20.05万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6778991
• 关键词: DNA binding protein; acute leukemia; affinity chromatography; antileukemic agent; cell line; chromosome translocation; gene targeting; mass spectrometry; neoplasm /cancer therapy; neoplastic cell; protein protein interaction; synthetic peptide; yeast two hybrid system

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.

描述（由申请人提供）：尽管白血病治疗，特别是在儿童的治疗方面取得了很大进展，但几个白血病仍然对治疗具有很高的抵抗力。 两种类型的抗性疾病，婴儿的急性白血病和附生植物毒素诱导的继发性白血病的特征是涉及位于11q23染色体的MLL基因的染色体易位。 在这两种情况下，相互易位会导致嵌合MLL融合基因的表达。 该提案的总体目的是检验以下假设：在这些类型的白血病中靶向基因产物的合成肽将有选择地抑制其生长。 本文提出的发现表明，MLL融合伙伴的羧基末端AF9与另一个MLL Fusion合作伙伴AF4的小域相互作用。 AF9和AF4的这些部分都存在于白血病相关的MLL融合蛋白中，这表明AF9和AF4能够以其天然形式和/或作为MLL融合蛋白相互作用。 MLL-AF4的物理互动 AF9在t（4; 11）（q21; q23）易位的细胞中可能很重要 婴儿白血病的特征。 已经开发出一个小的合成肽，破坏了体外AF4和AF9的相互作用。此外，肽特异性抑制了T（4; 11）白血病细胞系的增殖。 对人类健康很重要，这种肽或衍生物化合物可以提供一种独特的方法来治疗婴儿白血病或其他t（4; 11）重排的白血病患者。该研究项目的更具体的目标是检验肽结合AF9并破坏其与T（4; 11）白血病细胞中MLL-AF4的相互作用的假设。 我们预测，肽还结合缺乏T（4; 11）重排的白血病细胞中的AF9，但数据表明，天然蛋白质复合物的破坏对这些细胞的影响很小。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，以确定介导结合的临界接触点，从而为肽的合理设计提供基础，以阻止AF4-AF9结合。 最终，这些研究可能导致肽或相关化合物的发展，以有效治疗臭名昭著的困难人类疾病，包括婴儿白血病和与治疗相关的继发性白血病。