Targeted therapy for 11q23 acute leukemias

11q23急性白血病的靶向治疗

基本信息

批准号：
7848360
负责人：
Charles Stanley Hemenway
金额：
$ 20.3万
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 2013-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7848360
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 MLLT2 gene MLLT3 gene Macromolecular Complexes Mediating Multiprotein Complexes Mus Necrosis Nuclear Protein 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 public health relevance research study synthetic peptide t(4 11)(q21 q23)t(9 11)(p22 q23)therapy resistant tool treatment strategy

项目摘要

DESCRIPTION (provided by applicant): 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 th groundwork for pharmaceutical drug development. PUBLIC HEALTH RELEVANCE: This research project focuses on a newly described molecule that is selectively toxic to leukemia cell lines with rearrangements of the MLL gene. MLL leukemias are resistant to therapy and innovative approaches to treatment are important. In addition to assessing the utility of a new treatment, experiments are anticipated to reveal unique and important features of the biology of MLL leukemias.

描述（由申请人提供）：11q23染色体上MLL基因的重排预后预后不良的急性白血病。在5-10％的急性白血病中发现了MLL重排，并且在白血病和化学疗法相关的次要白血病中尤为常见。有必要为治疗MLL白血病治疗的新方法，因为越来越多的侵略性疗法仅带来了适度的生存改善。 MLL基因座的相互易位是异质的，但是两个最常见的转运伙伴是AF4和AF9基因。我们先前证明了AF4和AF9蛋白会形成多蛋白质复合物。此外，模仿AF4的AF9结合位点的小合成肽可以在体外和体内破坏蛋白质复合物。当暴露于一种此类肽时，指定为PFWT，表达MLL-AF4或MLL-AF9融合基因的白血病细胞系可能会因坏死而经历了编程的细胞死亡。重要的是，在对白血病细胞有毒的肽浓度上未观察到对骨髓菌落形成的影响。这些观察结果的一种可能的解释是，由AF4和AF9嵌合蛋白组成的大分子复合物对于T（4; 11）和T（9; 11; 11）白血病细胞的存活至关重要。通过结合AF9并破坏MLL-AF4-AF9（或MLL-AF9-AF4）蛋白复合物，PFWT抑制了MLL白血病。该研究项目的重点是AF4和AF9的相互作用域的作用，并将检查AF9与AF4或DOT1组蛋白甲基转移酶在白血病发生中结合的要求。通过分析特异性蛋白对嵌合癌蛋白活性的贡献，这些研究旨在揭示有希望的治疗MLL白血病的新方法。我们将PFWT肽设计为分子的原型，该原型阻断对白血病细胞存活至关重要的蛋白质相互作用。但是，我们也希望将实验工具的影响扩展到可行的治疗策略。因此，将在人类MLL白血病的小鼠模型中测试PFWT肽SPK-107的高度取代和更有效的衍生物。这些临床前研究旨在为药物开发奠定基础。公共卫生相关性：该研究项目的重点是新描述的分子，该分子对白血病细胞系有选择性地具有MLL基因的重排。 MLL白血病对治疗有抵抗力，而创新的治疗方法很重要。除了评估新处理的实用性外，还可以预计实验可以揭示MLL白血病生物学的独特而重要的特征。