The genetic and epigenetic cartography of multiple myeloma

项目摘要 基因和基因表达研究彻底改变了我们对浆细胞恶性肿瘤的理解 多发性骨髓瘤。因此，骨髓瘤的分子亚型得到了明确，高致死率的遗传标记也得到了明确。 风险疾病现在优先考虑患者进行风险适应治疗。然而，目前的分子标记无法识别 40%的高危患者在确诊后两年内复发或死亡。高危骨髓瘤的例证是 一种包含通常在标准风险中发现的基因改变的增殖基因表达亚型 子类型。因此，这种高风险的骨髓瘤不能用潜在的遗传事件来解释，这表明 表观遗传成分。表观遗传修饰如DNA甲基化(DNaM)调节基因表达 并提供对肿瘤抑制因子和癌基因活性的机械性洞察。重要的是，dNaM保持不变 通过细胞分裂，并能传播癌变表型。我们在老鼠身上的研究表明， 浆细胞分化过程中dNaM的重塑和DNA甲基转移酶活性的破坏 促进浆细胞增殖。然而，关于dNaM在高危骨髓瘤中的作用以及 增殖亚型。我们假设dNaM的失调导致了血管内皮细胞的不受控制的增殖。 高风险骨髓瘤。这将通过计算分析体细胞遗传变化来进行研究 全基因组测序，来自rna-seq的基因表达，以及来自全基因组的dNaM数据 对来自Commpass试验(NCT01454297)的392个样本进行了亚硫酸氢盐测序。在目标1中，我们将确定 由体细胞改变和基因表达确定的骨髓瘤亚型的dNaM程序。在这里，一个 重点将是阐明高风险增殖性疾病的表观遗传学程序。在目标2中，我们将确定 DNaM计划预测预后不良，并与复发标本中观察到的变化进行对比。 DNaM基因座与增殖性亚型、预后和复发时的重新编程相关 骨髓瘤将优先使用基于CRISPR的部位特异性表观遗传学编辑进行讯问。结果来自 这些目标将有助于解决侵袭性骨髓瘤和非侵袭性骨髓瘤中dNaM调节失调的功能后果 根据患者预后提供多发性骨髓瘤的分子图谱。从这项工作中获得的见解将 优先安排针对高危多发性骨髓瘤的后续翻译和机械性研究的途径。

Project Summary Genetic and gene expression studies have revolutionized our understanding of the plasma cell malignancy multiple myeloma. As a result, myeloma molecular subtypes have been defined, and genetic markers of high- risk disease now prioritize patients for risk-adapted therapies. Yet current molecular markers fail to identify over 40% of high-risk patients who relapse or die within two years of diagnosis. High-risk myeloma is exemplified by a proliferation gene expression subtype that contains genetic alterations normally found in standard-risk subtypes. Therefore, this high-risk myeloma is not explained by underlying genetic events suggesting an epigenetic component. Epigenetic modifications such as DNA methylation (DNAm) regulate gene expression and provide mechanistic insight into tumor suppressor and oncogene activity. Importantly, DNAm is maintained through cell division and can propagate cancerous phenotypes. Our studies in mice have shown a dramatic remodeling of DNAm during plasma cell differentiation, and that disruption of DNA methyltransferase activity promotes plasma cell proliferation. Yet there is limited data on the role of DNAm in high-risk myeloma and the proliferation subtype. We hypothesize that dysregulation of DNAm contributes to uncontrolled proliferation in high-risk myeloma. This will be investigated through computational analyses of somatic genetic alterations from whole genome sequencing, gene expression from RNA-seq, and DNAm data derived from whole genome bisulfite sequencing on 392 specimens from the CoMMpass trial (NCT01454297). In aim 1, we will determine the DNAm program of myeloma subtypes defined by both somatic alterations and gene expression. Here, a focus will be to elucidate the epigenetic program of high-risk proliferative disease. In aim 2, we will identify the DNAm program prognostic of poor outcome and contrast that with changes observed in relapsed specimens. DNAm loci associated with the proliferative subtype, prognostic of outcome, and reprogrammed in relapse myeloma will be prioritized for interrogation using CRISPR-based site-specific epigenetic editing. Results from these aims will help resolve the functional consequences of dysregulated DNAm in aggressive myeloma and provide a molecular map of multiple myeloma in the context of patient outcomes. Insights from this work will prioritize avenues for follow-up translational and mechanistic studies to target high-risk multiple myeloma.