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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.

项目总结