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.

尽管白血病的治疗，特别是儿童白血病的治疗取得了相当大的进展，但 白血病对治疗仍然具有高度耐药性。两种类型的耐药性疾病，婴儿急性白血病和 表鬼臼毒素引起的继发性白血病的特征是染色体易位，涉及 MLL基因位于染色体1lq23。在这两种情况下，相互易位都会导致 嵌合MLL融合基因的表达。该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将 选择性地抑制它们的生长。本文提出的结果表明 MLL 的羧基末端 融合伙伴 AF9 与另一个 MLL 融合伙伴 AF4 的一个小结构域相互作用。两者的这些部分 AF9 和 AF4 存在于白血病相关 MLL 融合蛋白中，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-的物理相互作用 AF4 和 AF9 可能在 t(4;11)(q21 ;q23) 易位细胞的白血病发生中发挥重要作用 是婴儿白血病的特征。一种小的合成肽已经被开发出来，可以破坏相互作用 olAF4 和 AF9 体外。此外，该肽还特异性抑制 (4;11) 白血病细胞的增殖 线。这种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 治疗婴儿白血病或其他具有 t(4;11) 重排的白血病患者。更具体的 该研究项目的目标是检验肽与 AF9 结合并破坏其相互作用的假设 t(4;11) 白血病细胞中的 MLL-AF4。我们预测该肽也会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 域来确定介导结合的关键接触点，为合理设计提供基础 阻断 AF4-AF9 结合的肽。最终，这些研究可能会导致肽或 用于有效治疗众所周知的人类疑难疾病（包括婴儿疾病）的相关化合物 白血病和治疗相关的继发性白血病。