Targeted therapy for 11q23 acute leukemias

11q23急性白血病的靶向治疗

• 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
• 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

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（申请人提供）：染色体11 q23处MLL基因重排预示着急性白血病患者预后不良。MLL重排在5-10%的急性白血病中发现，并且在患有白血病的婴儿和化疗相关的继发性白血病中特别常见。新的方法来治疗MLL白血病是必要的，因为越来越积极的治疗只产生了适度的改善生存。在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AF 4和AF 9基因。我们以前证明了AF 4和AF 9蛋白形成多蛋白复合物。此外，蛋白质复合物可以在体外和体内被模拟AF 4的AF 9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-AF 4或MLL-AF 9融合基因的白血病细胞系通过坏死经历程序性细胞死亡。重要的是，在对白血病细胞有毒性的肽浓度下未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AF 4和AF 9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AF 9并破坏MLL-AF 4-AF 9（或MLL-AF 9-AF 4）蛋白复合物，PFWT抑制MLL白血病。本研究项目的重点是AF 4和AF 9的相互作用结构域的作用，并将检查AF 9与AF 4或Dot 1组蛋白甲基转移酶在白血病发生中的结合要求。通过分析特定蛋白质对嵌合癌蛋白活性的贡献，这些研究旨在揭示有希望的治疗MLL白血病的新方法。我们已经设计了PFWT肽作为阻断对白血病细胞存活至关重要的蛋白质相互作用的分子的原型。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。公共卫生关系：该研究项目的重点是一种新描述的分子，该分子对MLL基因重排的白血病细胞系具有选择性毒性。MLL白血病对治疗具有抗性，因此创新的治疗方法非常重要。除了评估新疗法的效用外，预计实验将揭示MLL白血病生物学的独特和重要特征。