Targeted therapy for 11q23 acute leukemias

描述(申请人提供)：染色体11q23的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%的急性白血病中被发现，在白血病婴儿和化疗相关的继发性白血病中尤其常见。治疗MLL白血病的新方法是有必要的，因为越来越积极的治疗只产生了适度的生存改善。MLL基因的相互易位是异质性的，但最常见的两个易位伙伴是AF4和AF9基因。我们先前证明了AF4和AF9蛋白形成一个多蛋白复合体。此外，在体外和体内，这种蛋白质复合体都可以被模拟AF4的AF9结合位点的小分子合成肽破坏。表达MLL-AF4或MLL-AF9融合基因的白血病细胞株在暴露于一种名为PFWT的多肽时，会发生细胞程序性死亡，导致细胞坏死。重要的是，在对白血病细胞有毒性的多肽浓度下，观察不到对骨髓集落形成的影响。这些观察结果的一个可能的解释是，由AF4和AF9嵌合蛋白组成的大分子复合体对t(4；11)和t(9；11)白血病细胞的生存至关重要。通过结合AF9和破坏MLL-AF4-AF9(或MLL-AF9-AF4)蛋白复合体，PFWT抑制MLL白血病。这项研究的重点是AF4和AF9相互作用结构域的作用，并将研究AF9与AF4或Dot1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白血病的有前途的新方法。我们设计了PFWT多肽作为阻断对白血病细胞生存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，一种高取代和更有效的PFWT多肽衍生物SPK-107将在人MLL白血病的小鼠模型中进行测试。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：这项研究项目集中在一种新描述的分子上，这种分子通过MLL基因的重排对白血病细胞株具有选择性毒性。MLL白血病对治疗具有抵抗力，创新的治疗方法很重要。除了评估一种新治疗方法的有效性外，预计实验还将揭示MLL白血病生物学的独特和重要特征。

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.