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 多发性骨髓瘤是一种浆细胞癌症，每年导致超过12，000名美国人死亡。遗传改变 在骨髓瘤中，包括大多数奇数染色体的三体性，导致异位表达的易位 癌基因以及癌基因和肿瘤抑制基因的结构变体和突变。这些 不同的遗传改变表现为独特的分子亚型。结果的显著改善 使用包括蛋白酶体抑制剂、沙利度胺类似物（统称为 免疫调节酰亚胺药物（IMiD）和免疫疗法。不幸的是，大多数患者仍然发展 一种难以治疗的疾病，最后死于骨髓瘤。这些一线疗法的使用， 以及它们在所有骨髓瘤中是否同样有效还不完全清楚。这是 我们最近的研究强调，免疫球蛋白轻链λ（IGL）易位是 预测IMiD反应较差。IMiD介导淋巴细胞转录因子的降解 IKAROS和AIOLOS。有趣的是，IGL增强子与一些最高水平的IKAROS结合， 骨髓瘤表观基因组这表明IKAROS和AIOLOS活性在基因组中的位置和水平 指示IMiD响应。为了验证IKAROS和AIOLOS结合的基因组元件 确定IMiD反应，并且这些区域在骨髓瘤遗传亚型之间变化，以下目的是 提出了1)IKAROS和AIOLOS基因组结合位点将被确定并在IMiD之间进行比较。 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。 耐药骨髓瘤结合起来，IKAROS和AIOLOS结合区域的表观遗传学程序将是 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 这些元素以及对基因表达的影响。2)IKAROS和AIOLOS将分别在 使用CRISPR干扰抑制，并将评估所得的表型和分子影响， 确定每个因素对IMiD响应的贡献。3)IKAROS和AIOLOS结合的基因组元件 将被系统地破坏，以测试这些调节元件在介导IMiD抗性中的功能。 候选人的长期目标是运行一个独立的研究项目，调查病因 并将发现转化为更好的治疗靶向和患者结果。上述目标将 为建立独立的研究计划提供了一个框架。上述目标也适用于 创新的新方法来发现IMiDs发挥其治疗作用的机制以及为什么 一些骨髓瘤变得对IMiD耐药，这是多发性骨髓瘤死亡的主要原因。