Validation of Critical 1q21 Vulnerabilities in Multiple Myeloma

项目总结 1q21的扩增定义了一种最常见的多发性骨髓瘤(MM)亚型 预后。1q21扩增子包含许多基因，虽然不太可能所有基因都对 高危MM的病理生物学，驱动这种高危表型的关键基因还没有完全被发现 澄清了。识别这些基因及其对这种表型的贡献将使新的 对高危多发性骨髓瘤采取有效的靶向治疗策略，从而改善其生存结果。在这 应用，我们建议研究1q21背后的生物学和分子机制。 扩增对高危多发性骨髓瘤的贡献，最终目标是获得一份有效的治疗方案清单 目标是为这一亚组患者设计新的转化性临床试验。在预赛中 功能基因组学研究，我们发现了5个1q21必需基因，它们的丢失会导致MM细胞死亡和/或 生长抑制。我们对其中一个基因ILF2(白介素增强子结合)的初步机制研究 因子2)，提示该基因参与了dna损伤反应的调节，并介导药物。 对遗传毒性药物的耐药性呈剂量依赖关系，这可能解释了为什么1q21多发性骨髓瘤患者受益 与非1q21多发性骨髓瘤患者相比，大剂量化疗所产生的副作用更少。根据这些数据，我们假设 我们已经确定的五个1q21候选基因对高危多发性骨髓瘤有重要贡献 表型，这些关键的1q21漏洞的临床前验证将产生新的治疗方法 这些患者的目标。为了验证这些假设，我们将追求以下三个具体目标：1) 剖析1q21基因候选在高危多发性骨髓瘤发病中的分子机制 表型，我们将对这些候选进行体外功能验证研究，使用 人类多发性骨髓瘤细胞系、原代多发性骨髓瘤样本和异种移植模型的基因组学特征。2)识别 1q21基因候选在多发性骨髓瘤体内发病机制中的作用，我们将采用一种新的、生理上相关的 一种以这些基因在生发中心细胞中表达为目标的遗传学方法，被认为是... 多发性骨髓瘤浆细胞的起源。3)为了确定针对ILF2的治疗的可行性，我们将 与Ionis制药公司合作开发针对ILF2和功能的反义寡核苷酸 验证其单独或联合DNA损伤剂抑制多发性骨髓瘤的有效性 临床前播散性MM小鼠移植模型的生长/进展 拟议的研究不仅将扩大我们对1q21基因在MM病理生物学中的作用的理解，而且 还告知开发新的有针对性的方法，以改善患有多发性骨髓瘤患者的预后 对我们批准的治疗药物难以治愈的高危疾病。

PROJECT SUMMARY Amplification of 1q21 defines one of the most common multiple myeloma (MM) subtypes with an adverse prognosis. The 1q21 amplicon contains many genes, and while it is unlikely that all contribute to the pathobiology of high-risk MM, the critical genes that do drive this high-risk phenotype have not yet been fully clarified. Identifying such genes and their contributions to this phenotype would enable the development of new and effective targeted therapy strategies for high-risk MM and thus improve their survival outcomes. In this application, we propose to investigate the biological and molecular mechanisms behind the 1q21 amplification's contribution to high-risk MM with the ultimate goal of obtaining a list of validated therapeutic targets to inform the design of novel translational clinical trials for this subgroup of patients. In preliminary functional genomic studies, we identified five 1q21 essential genes whose loss results in MM cell death and/or growth inhibition. Our initial mechanistic studies of one of these genes, ILF2 (interleukin enhancer binding factor 2), suggest that the gene is involved in the regulation of the DNA damage response and mediates drug resistance to genotoxic agents in a dose-dependent manner, which may explain why 1q21 MM patients benefit less from high-dose chemotherapy than non–1q21 MM patients do. On the basis of these data, we hypothesize that the five 1q21 gene candidates we have identified make essential contributions to the high-risk MM phenotype and that the preclinical validation of these critical 1q21 vulnerabilities will yield novel therapeutic targets for these patients. To test these hypotheses, we will pursue the following three specific aims: 1) To dissect the molecular mechanisms underlying 1q21 gene candidates' contributions to the high-risk MM phenotype, we will subject these candidates to in vitro functional validation studies using a panel of genomically characterized human MM cell lines, primary MM samples, and xenograft models. 2) To identify 1q21 gene candidates' roles in MM pathogenesis in vivo, we will employ a novel, physiologically relevant genetic approach that targets these genes' expression in the germinal center cells, considered to be the cell-of- origin of MM plasma cells. 3) To determine the feasibility of therapeutically targeting ILF2, we will collaborate with IONIS Pharmaceuticals to develop antisense oligonucleotides targeting ILF2 and functionally validate their effectiveness both alone and in combination with DNA-damaging agents in inhibiting MM growth/progression in preclinical xenograft mouse models of disseminated MM. We anticipate that the proposed study will not only expand our understanding of 1q21 genes' contributions to MM pathobiology but also inform the development of new targeted approaches to improve the outcomes of MM patients who have high-risk disease that is refractory to our approved therapeutic agents.