Targeted therapy for 11q23 acute leukemias.

11q23急性白血病的靶向治疗。

• 批准号: 7391927
• 负责人: Charles Stanley Hemenway
• 金额: $ 9.31万
• 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 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7391927
• 关键词: 11q23; 4q21; 9p22; AF-9 protein; Acute leukemia; Affinity; Affinity Chromatography; Amino Acid Substitution; Binding; Cell Line; Cells; Characteristics; Child; Chimeric Proteins; Chromosomal translocation; Chromosomes; Complex; DNA Sequence Rearrangement; Data; Development; Disease Resistance; Disruption; Epipodophyllotoxin Compound; Exhibits; Exposure to; Generations; Genes; Goals; Growth; Health; Human; In Vitro; Infant; Intervention; Laboratories; Lead; Link; MLL gene; MLLT2 gene; MLLT3 gene; Mass Spectrum Analysis; Mediating; Methods; Mutation; Numbers; Patients; Peptides; Property; Protein Binding; Proteins; Reciprocal Translocation; Recommendation; Research Personnel; Research Project Grants; Resistance; Testing; Yeasts; alpha-Thalassemia; base; chemotherapy; design; fusion gene; human disease; insight; leukemia; leukemogenesis; prevent; programs; synthetic peptide; t(4; 11)(q21; q23); yeast two hybrid system

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.

尽管在白血病治疗，特别是在儿童中的治疗方面取得了很大进展，但几个子集的 白血病仍然对治疗具有很高的耐药性。两种类型的抗性疾病，婴儿的急性白血病和 附生植物毒素指的次级白血病的特征是染色体转移涉及涉及 位于1LQ23染色体的MLL基因。在这两个方面，相互易位导致 嵌合MLL融合基因的表达。该提议的总体目的是检验假设 在这些类型的白血病中唯一表达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的羧基末端 Fusion合作伙伴AF9与另一个MLL Fusion合作伙伴AF4的小域进行互动。两者的这些部分 白血病相关的MLL融合蛋白中存在AF9和AF4，表明AF9和AF4是 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 AF4具有AF9在t（4; 11）（q21; q23）易位细胞中的白血病中很重要 婴儿白血病的特征。已经开发了一个小的合成肽，破坏了相互作用 OLAF4和AF9体外。此外，肽特异性抑制了t（4; 11）白血病细胞 线。对人类健康很重要，这种肽或衍生化合物可以提供独特的手段 治疗婴儿白血病或其他白血病患者进行T（4; 11）重排。更具体 该研究项目的目标是检验肽结合AF9并破坏其相互作用的假设 T（4; 11）白血病细胞中的MLL-AF4。我们预测该肽还结合白血病细胞中的AF9 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AF4-AF9蛋白相互作用进行广泛的突变分析 域以确定介导约束以提供理性设计的关键接触点 肽可以阻止AF4-AF9结合。最终，这些研究可能导致肽的发展或 有效治疗包括婴儿在内的臭名昭著的困难人类疾病的相关化合物 白血病和与治疗有关的次要白血病。