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）：染色体 11q23 处 MLL 基因的重排预示着急性白血病患者的预后不良。 MLL 重排存在于 5-10% 的急性白血病中，并且在患有白血病的婴儿和化疗相关的继发性白血病中尤其常见。由于越来越积极的治疗仅对生存率产生了有限的改善，因此需要新的 MLL 白血病治疗方法。 MLL 基因座的相互易位是异质的，但两个最常见的易位伴侣是 AF4 和 AF9 基因。我们之前证明 AF4 和 AF9 蛋白形成多蛋白复合物。此外，该蛋白质复合物可以在体外和体内被模拟 AF4 的 AF9 结合位点的小合成肽破坏。当暴露于一种这样的肽（称为 PFWT）时，表达 MLL-AF4 或 MLL-AF9 融合基因的白血病细胞系会因坏死而发生程序性细胞死亡。重要的是，在对白血病细胞有毒的肽浓度下，没有观察到对骨髓集落形成的影响。对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) 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 可抑制 MLL 白血病。该研究项目重点关注 AF4 和 AF9 相互作用域的作用，并将研究 AF9 与 AF4 或 Dot1 组蛋白甲基转移酶结合在白血病发生中的需求。通过分析特定蛋白质对嵌合癌蛋白活性的贡献，这些研究旨在揭示治疗 MLL 白血病的有前景的新方法。我们设计了 PFWT 肽作为分子原型，可阻断对白血病细胞存活至关重要的蛋白质相互作用。然而，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MLL白血病的小鼠模型中测试PFWT肽的高度取代且更有效的衍生物SPK-107。这些临床前研究旨在为药物开发奠定基础。公共健康相关性：该研究项目重点关注一种新描述的分子，该分子对 MLL 基因重排的白血病细胞系具有选择性毒性。 MLL 白血病对治疗有抵抗力，创新的治疗方法非常重要。除了评估新疗法的实用性之外，实验预计还将揭示 MLL 白血病独特而重要的生物学特征。