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

揭示 IMiD 在多发性骨髓瘤中的顺式调节功能。

• 批准号: 10525980
• 负责人: Benjamin Gabriel Barwick
• 金额: $ 18.74万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-12-07 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10525980
• 关键词: Ablation; Acceleration; Affect; Antibodies; Binding; Binding Proteins; Binding Sites; CRISPR interference; CRISPR-mediated transcriptional activation; Cancer Etiology; Cells; Cessation of life; ChIP-seq; Chromatin; Chromosomes; Cyclin D1; DNA Sequence Alteration; Data; Defect; Dependence; Diagnosis; Disease; Drug resistance; Ectopic Expression; Elements; Enhancers; Epigenetic Process; Event; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Growth; Heavy-Chain Immunoglobulins; Imides; Immunotherapy; In Situ; Individual; Infection; Light-Chain Immunoglobulins; Location; Lymphocyte; Malignant Neoplasms; Measures; Mediating; Modality; Molecular; Molecular Target; Multiple Myeloma; Mutation; Newly Diagnosed; Oncogenes; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phenotype; Plasma Cells; Positioning Attribute; Proliferating; Proteasome Inhibitor; Proto-Oncogenes; Refractory; Regulator Genes; Regulatory Element; Research; Resistance; Resistance development; Role; Running; Scientist; Specimen; Testing; Thalidomide; Therapeutic; Therapeutic Effect; Translating; Trisomy; Tumor Suppressor Genes; Validation; Variant; Work; analog; career; cell growth; drug sensitivity; drug-sensitive; epigenome; experimental study; gene repression; genomic data; histone methyltransferase; histone modification; immunoregulation; improved; in vivo Model; innovation; insight; molecular subtypes; mortality; next generation sequencing; novel strategies; overexpression; prognostic; programs; promoter; response; therapeutic target; transcription factor; transcriptome sequencing; treatment response

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.

项目摘要 多发性骨髓瘤是血浆细胞的癌症，每年导致12,000多人死亡。遗传改变 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 癌基因以及肿瘤基因和肿瘤抑制基因的突变的结构变异。这些 独特的遗传改变表现为独特的分子亚型。结果的重大改善 是使用包括蛋白酶体抑制剂的疗法，沙利度胺 - 纳尔氏菌共同被称为 免疫调节性伊酰亚胺药物（IMID）和免疫疗法。不幸的是，大多数患者仍在发展 难治性并屈服于骨髓瘤的疾病。这些前线疗法均被使用 骨髓瘤亚型以及它们在所有骨髓瘤中是否同样有效的含量尚未完全了解。这是 我们最近的研究强调了免疫球蛋白轻链Lambda（IGL）易位 预测不良反应。 iMIDS介导淋巴细胞转录因子的降解 Ikaros和Aiolos。有趣的是，IGL增强子受到某些最高水平的Ikaros的约束 骨髓瘤表观基因组。这表明基因组中的ikaros和蒜泥活性的位置和水平 决定imid的回应。检验以下假设：基因组元素由ikaros和Aiolos绑定 确定IMID反应，这些区域在骨髓瘤遗传亚型之间有所不同。以下目的是 建议的。 1）将确定并比较ikaros和Aiolos基因组结合位点 敏感和耐药性骨髓瘤细胞，以查看这些因素是否本地化于基因组的不同区域 抗骨髓瘤。同时，Ikaros-和Aiolos结合区域的表观遗传计划将是 在基线和IMID处理的条件下进行表征，以识别Ikaros和Aiolos耗竭如何影响 这些元素以及结果对基因表达的影响。 2）Ikaros和Aiolos每个人都会 使用CRISPR干扰抑制以及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响应的贡献。 3）Ikaros-和Aiolos结合的基因组元素 将系统中断，以测试这些调节元素在介导IMID抗性中的功能。 候选人的长期目标是开展一项独立研究计划，以调查病因 癌症并将发现转化为更好的治疗靶向和患者结局。以上目标将 提供一个建立独立研究计划的框架。以上目的也将适用 创新的新方法，以发现Imids发挥其治疗作用的机制以及为什么 一些骨髓瘤变成抗imid，这是多发性骨髓瘤死亡率的主要原因。