The genetic and epigenetic cartography of multiple myeloma

多发性骨髓瘤的遗传和表观遗传制图

基本信息

批准号：
10648380
负责人：
Benjamin Gabriel Barwick
金额：
$ 21万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10648380
关键词：
Antibodies B cell differentiation Binding Sites Biology Cancerous Cell Line Cell Proliferation Cell division Cell secretion Cessation of life Chromosomes Clinical Data Clustered Regularly Interspaced Short Palindromic Repeats Computer Analysis Coupled DNA DNA Integration DNA Methylation DNA Modification Methylases DNA Sequence Alteration Data Diagnosis Disease Disease Outcome Epigenetic Process Event Exhibits Foundations Gene Expression Genes Genetic Genetic Markers Genetic Transcription Genomics Heritability Malignant Neoplasms Maps Mitotic Modeling Modification Molecular Multiple Myeloma Multivariate Analysis Mus Mutation Newly Diagnosed Oncogenes Outcome Pathway interactions Patient risk Patient-Focused Outcomes Patients Phenotype Plasma Cells Prognostic Factor Prognostic Marker Proliferating Refractory Regulator Genes Relapse Risk Role Sampling Site Specimen Testing Therapeutic Training Tumor Suppressor Proteins Untranslated RNA Validation Work adaptive immunity adverse outcome bisulfite sequencing cancer risk disorder risk early experience epigenetic regulation follow-up genetic architecture genome sequencing high risk insight molecular marker molecular subtypes patient stratification plasma cell differentiation prognostic prognostic of survival programs response secondary analysis transcription factor transcriptome sequencing translational study tumor DNA whole genome

项目摘要

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.

项目摘要遗传和基因表达研究彻底改变了我们对等离子体细胞恶性肿的理解多发性骨髓瘤。结果，已经定义了分子亚型的骨髓瘤，高位的遗传标志物现在，风险疾病现在将患者的风险适应疗法置于优先级。但是当前的分子标记无法识别在诊断后的两年内复发或死亡的高危患者中有40％。高风险骨髓瘤被举例说明增殖基因表达亚型，其中包含通常在标准风险中发现的遗传变量亚型。因此，这种高风险骨髓瘤并未通过暗示的基本遗传事件来解释表观遗传成分。表观遗传修饰（例如DNA甲基化（DNAM））调节基因表达并提供有关抑制肿瘤和癌基活性的机械洞察力。重要的是，DNAM被维护通过细胞分裂，可以传播癌性表型。我们在小鼠中的研究表明了一个戏剧性的血浆细胞分化过程中DNAM的重塑，并破坏DNA甲基转移酶活性促进血浆细胞增殖。然而，关于DNAM在高风险骨髓瘤和增殖亚型。我们假设DNAM的失调有助于不受控制的增殖高风险骨髓瘤。这将通过计算分析的躯体遗传改变的计算分析整个基因组测序，RNA-Seq的基因表达以及源自整个基因组的DNAM数据来自CommPass试验的392个标本（NCT01454297）进行的Bisulfite测序。在AIM 1中，我们将确定由体细胞改变和基因表达定义的骨髓瘤亚型的DNAM程序。在这里，重点是阐明高风险增殖性疾病的表观遗传计划。在AIM 2中，我们将确定 DNAM计划的预后不良结果和与复发标本中观察到的变化对比。 DNAM基因座与增生性亚型相关，预后的结果，并在复发中重新编程使用基于CRISPR的特定地点表观遗传学编辑，将优先考虑骨髓瘤进行询问。结果这些目标将有助于解决侵略性骨髓瘤和在患者结局的背景下，提供多发性骨髓瘤的分子图。这项工作的见解将优先考虑途径进行随访的转化和机械研究，以靶向高风险的多发性骨髓瘤。