Revealing the cis-Regulatory Function of IMiDs in Multiple Myeloma”.

项目摘要 多发性骨髓瘤是一种浆细胞癌，每年导致美国超过12000人死亡。基因改变 在骨髓瘤中包括大多数奇数染色体的三体，导致异位表达的易位 癌基因以及癌基因和抑癌基因的结构变异和突变。这些 独特的遗传改变表现为独特的分子亚型。在结果方面有了显著的改善 使用的疗法包括蛋白酶体抑制剂，沙利度胺类似物统称为 免疫调节性亚胺类药物(IMids)和免疫疗法。不幸的是，大多数患者仍在 难以治疗并死于骨髓瘤的疾病。这些一线疗法不管怎样都在使用 对于骨髓瘤亚型，以及它们在所有骨髓瘤中是否同样有效，目前还不完全清楚。这是 我们最近的研究表明免疫球蛋白轻链Lambda(IGL)易位是 预示着不良的IMiD反应。IMID介导淋巴细胞转录因子的降解 伊卡洛斯和奥洛斯。有趣的是，IGL增强子被一些最高水平的IKAROS结合 骨髓瘤表观基因组。这表明IKAROS和AIOLOS在基因组中的位置和活性水平 口述IMID响应。检验IKAROS和AIOLOS结合的基因组元件的假设 确定IMIDD反应和这些区域在骨髓瘤遗传亚型之间的差异 建议。1)将测定并比较IMIDD-Im和Im-D-Im之间的IKAROS和AIOLOS基因组结合位点。 敏感和耐药的骨髓瘤细胞，看看这些因子是否定位于IMiD基因组的不同区域- 耐药骨髓瘤。同时，IKAROS和AIOLOS结合区的表观遗传计划将是 在基线和IMID治疗条件下进行表征，以确定IKAROS和AIOLOS耗竭如何影响 这些元素以及由此对基因表达的影响。2)IKAROS和AIOLOS将分别是 使用CRISPR干扰抑制和由此产生的表型和分子影响将被评估为 确定每个因素对IMID反应的贡献。3)IKAROS和AIOLOS结合的基因组元件 将被系统干扰，以测试这些调节元件在调节IMiD抵抗中的功能。 候选人的长期目标是运行一项独立的研究计划，调查病因学 并将研究结果转化为更好的治疗靶点和患者结果。上述目标将 为建立独立的研究计划提供框架。上述目标也将适用 发现IMIDS发挥治疗效果的机制及其原因的创新新方法 一些骨髓瘤对IMID产生耐药性，这是多发性骨髓瘤死亡的主要原因。

Project Summary Multiple myeloma is a cancer of plasma cells resulting in over 12,000 U.S. deaths each year. Genetic alterations in myeloma include trisomy of most odd-numbered chromosomes, translocations that result in ectopic expression of oncogenes as well as structural variants and mutations in oncogenes and tumor suppressor genes. These distinct genetic alterations manifest as unique molecular subtypes. Significant improvements in outcomes have been made using therapies including proteasome inhibitors, thalidomide-analogs collectively known as immunomodulatory imide drugs (IMiDs), and immunotherapies. Unfortunately, most patients still develop disease that is refractory to treatment and succumb to myeloma. These frontline therapies are used regardless of myeloma subtype and whether they are equally effective in all myelomas is not fully understood. This is underscored by our recent study identifying Immunoglobulin Light Chain Lambda (IGL) translocations as predictive of poor IMiD responses. IMiDs mediate the degradation of the lymphocyte transcription factors IKAROS and AIOLOS. Interestingly, the IGL enhancer was bound by some of the highest levels of IKAROS in the myeloma epigenome. This suggests that location and levels of IKAROS and AIOLOS activity in the genome dictate IMiD responses. To test the hypothesis that the genomic elements bound by IKAROS and AIOLOS determine IMiD response and that these regions vary between myeloma genetic subtypes the following aims are proposed. 1) IKAROS and AIOLOS genomic binding sites will be determined and compared between IMiD- sensitive and -resistant myeloma cells to see if these factors localize to distinct regions of the genome in IMiD- resistant myeloma. In conjunction, the epigenetic program of IKAROS- and AIOLOS-bound regions will be characterized under baseline and IMiD-treated conditions to identify how IKAROS and AIOLOS depletion affects these elements as well as the resultant impact on gene expression. 2) IKAROS and AIOLOS will each be inhibited using CRISPR interference and the resultant phenotypic and molecular impact will be assessed to determine the contribution of each factor to IMiD responses. 3) IKAROS- and AIOLOS-bound genomic elements will be systematically disrupted to test the function of these regulatory elements in mediating IMiD resistance. The long-term goals of the candidate are to run an independent research program investigating the etiology of cancer and translate findings into better therapeutic targeting and patient outcomes. The above aims will provide a framework for establishing an independent research program. The above aims will also apply innovative new approaches to discover the mechanism by which IMiDs exert their therapeutic effects and why some myelomas become IMiD resistant, a major cause of multiple myeloma mortality.