Targeted therapy for 11q23 acute leukemias

11q23急性白血病的靶向治疗

基本信息

批准号：
8270564
负责人：
Charles Stanley Hemenway
金额：
$ 19.69万
依托单位：
LOYOLA UNIVERSITY CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-04-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8270564
关键词：
11q23 4q21 9p22 AF-9 protein Acute leukemia Apoptosis Binding Binding Sites Biological Process Biology Bone Marrow Cell Line Cell Survival Cells Characteristics Chimeric Proteins Chromosomal translocation Complex DNA Sequence Rearrangement Data Disease Epipodophyllotoxin Compound Exhibits Exposure to Gene Expression Generations Genes HOXA9 gene Human In Vitro Infant Intervention Laboratories Link MLL gene MLL-AF9 MLLT2 gene MLLT3 gene Macromolecular Complexes Mediating Multiprotein Complexes Mus Necrosis Nuclear Proteins Oncogene Proteins Patients Peptides Pharmaceutical Preparations Pharmacologic Substance Positive Transcriptional Elongation Factor B Property Proteins Reciprocal Translocation Research Design Research Project Grants Resistance Role Testing Transcription Elongation Xenograft Model aggressive therapy alpha-Thalassemia chemotherapy cytotoxic drug development fusion gene histone methyltransferase in vivo innovation insight leukemia leukemogenesis macromolecular assembly mouse model mutant novel strategies outcome forecast preclinical study protein complex prototype research study synthetic peptide t(4 11)(q21 q23)t(9 11)(p22 q23)therapy resistant tool treatment strategy

项目摘要

PROJECT SUMMARY Rearrangements of the MLL gene at chromosome 11q23 portend a poor prognosis in patients with acute leukemia. MLL rearrangements are found in 5-10% of acute leukemias and are particularly common both in babies with leukemia and in chemotherapy-associated secondary leukemia. New approaches to the treatment of MLL leukemia are warranted as increasingly aggressive therapy has yielded only modest improvements in survival. Reciprocal translocations at the MLL locus are heterogeneous, but the two most common translocation partners are the AF4 and AF9 genes. We previously demonstrated that AF4 and AF9 proteins form a multiprotein complex. Moreover, the protein complex can be disrupted in vitro and in vivo by small synthetic peptides that mimic the AF9 binding site of AF4. When exposed to one such peptide, designated PFWT, leukemia cell lines expressing MLL-AF4 or MLL-AF9 fusion genes undergo programmed cell death by necrosis. Importantly, no effect on bone marrow colony formation is observed at peptide concentrations that are toxic to leukemia cells. One possible explanation for these observations is that macromolecular complexes comprised of AF4 and AF9 chimeric proteins are crucial for the survival of t(4;11) and t(9;11) leukemia cells. By binding AF9 and disrupting MLL-AF4-AF9 (or MLL-AF9-AF4) protein complexes, PFWT inhibits MLL leukemias. This research project focuses on the role of the mutual interaction domains of AF4 and AF9 and will examine the requirement for binding of AF9 to AF4 or to Dot1 histone methyltransferase in leukemogenesis. By analyzing the contributions of specific proteins to the activity of chimeric oncoproteins, these studies are designed to reveal promising new approaches to treat MLL leukemia. We have devised the PFWT peptide as a prototype of molecules that block protein interactions critical to leukemia cell survival. However, we also hope to extend the impact of experimental tools to feasible treatment strategies. Thus, a highly substituted and more potent derivative of PFWT peptide, SPK- 107, will be tested in a mouse model of human MLL leukemia. These pre-clinical studies are intended to lay the groundwork for pharmaceutical drug development.

项目摘要 11q23染色体上MLL基因的重排预后预后不良与急性白血病。在5-10％的急性白血病中发现了MLL重排，是在白血病和化学疗法相关的次级中，尤其是常见的白血病。有必要越来越多的新方法来治疗MLL白血病积极的疗法仅在生存方面得到适度的改善。 MLL基因座的相互易位是异质的，但两个最常见的转运伙伴是AF4和AF9基因。我们以前证明了AF4和AF9 蛋白质形成多蛋白复合物。此外，蛋白质复合物可以在体外和小型合成肽的体内模仿AF4的AF9结合位点。当暴露于这样一个肽，指定的PFWT，表达MLL-AF4或MLL-AF9融合基因的白血病细胞系通过坏死经历了程序性细胞死亡。重要的是，对骨髓菌落形成没有影响在对白血病细胞有毒的肽浓度下观察到。这些观察结果的一种可能的解释是，大分子复合物包括 AF4和AF9嵌合蛋白的生存至关重要。经过 BIND AF9并破坏MLL-AF4-AF9（或MLL-AF9-AF4）蛋白复合物，PFWT抑制MLL 白血病。该研究项目的重点是AF4和 AF9并将检查AF9与AF4或DOT1组蛋白甲基转移酶结合的要求在白血病中。通过分析特定蛋白质对嵌合癌蛋白活性的贡献，这些研究旨在揭示有希望治疗MLL白血病的新方法。我们有将PFWT肽设计为分子的原型，阻止蛋白质相互作用至关重要白血病细胞存活。但是，我们也希望将实验工具的影响扩展到可行治疗策略。因此，PFWT肽，SPK-的高度取代，更有效的衍生物 107将在人类MLL白血病的小鼠模型中进行测试。这些临床前研究是旨在为药物开发奠定基础。