C/EBPJ3 in bone marrow stromal cell-mediated drug resistance of multiple myeloma

C/EBPJ3在骨髓基质细胞介导的多发性骨髓瘤耐药中的作用

• 批准号: 10620611
• 负责人: Gangqing Hu
• 金额: $ 26.37万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10620611
• 关键词: Aftercare; B-Lymphocytes; Binding; Biological Process; Bone Marrow; Cell Line; Cell Survival; Cells; ChIP-seq; Chromatin; Coculture Techniques; Conditioned Culture Media; Data; Disease; Drug resistance; Engraftment; Epigenetic Process; Gene Expression; Genes; Genetic Transcription; Genomics; Goals; Growth; Hematologic Neoplasms; Human; Immune; Immunomodulators; Laboratories; Leucine Zippers; Malignant - descriptor; Mediating; Multi-Drug Resistance; Multiple Myeloma; Osteoblasts; Plasma; Play; Proliferating; Research; Research Subjects; Role; Signal Pathway; Signaling Protein; Stromal Cells; Transcriptional Regulation; Tumor Burden; XCL1 gene; cancer cell; embryonic stem cell; epigenetic regulation; experience; genome-wide; in vivo; lenalidomide; mouse model; multiple omics; overexpression; pomalidomide; protective effect; response; stem; transcriptome; transcriptome sequencing; tumor; tumor microenvironment

Epigenetic regulation plays a critical role in numerous biological processes. The overarching goal of my laboratory is to understand epigenetic mechanisms of drug resistance of hematological cancers in the bone marrow (BM) microenvironment. I have over 12 years of research experience on transcription regulation of chromatin regulators in immune cells, embryonic stem cells, and cancer cells. This proposal is to investigate the transcription-regulatory role of a leucine-zipper TF C/EBPβ in promoting de novo drug resistance of Multiple Myeloma (MM) in the BM microenvironment. MM is a disease caused by malignant plasma B cells mainly proliferating in the BM. It is incurable largely because of the emergence of drug resistance after treatments. One important contribution to drug resistance stems from the protective effect of the BM microenvironment, which includes growth promoting soluble factors and physical interaction with cellular components such as stromal cells and osteoblasts. The emergence of de novo drug resistance occurs in a short timeframe and is reversible, suggesting epigenetic mechanisms as an important contributor. However, the identities and mechanisms of chromatin regulators contributing to de novo drug resistance of MM in the BM microenvironment remain largely unexplored. Our preliminary results indicated C/EBPβ as a key transcription regulator of target genes of signaling pathways activated by BM stromal cells. The BM stromal cells induced a genome-wide reprogramming in gene expression (transcriptome) and chromatin accessibility (regulome) of MM cells, turned out being mainly driven by soluble factors. Integrative analysis with ENCODE genomic binding data indicated C/EBPβ as a major contributor to the BM stromal cellinduced transformation of transcriptome and regulome. As C/EBPβ- overexpression protects MM cells from IMiD compounds, our preliminary results defined C/EBPβ as a promising and new research subject to understand epigenetic mechanisms for the emergence of de novo drug resistance in MM. We hypothesize that C/EBPβ contributes to soluble factor-mediated drug resistance by transcriptionally regulating target genes of growth-promoting signaling pathways activated by BM stromal cells through

表观遗传调控在许多生物过程中起着关键作用。我的首要目标是 实验室是为了了解骨部血液病耐药的表观遗传机制 骨髓微环境。我在转录调控方面有超过12年的研究经验 免疫细胞、胚胎干细胞和癌细胞中的染色质调节剂。这项建议是为了调查 亮氨酸拉链TfC/eBPβ在促进新药耐药中的转录调节作用 骨髓微环境中的多发性骨髓瘤(MM)多发性骨髓瘤是一种由恶性血浆B细胞引起的疾病 主要在骨髓中增殖。它是无法治愈的，很大程度上是因为在 治疗。造成耐药性的一个重要因素是BM的保护作用 微环境，包括促进生长的可溶性因子和与细胞的物理相互作用 基质细胞和成骨细胞等成分。新药耐药性的出现发生在 时间很短，而且是可逆的，表明表观遗传机制是一个重要因素。 然而，染色质调节因子在新发耐药中的地位和作用机制 BM微环境中的MM在很大程度上仍未被探索。我们的初步结果表明C/eBPβ是一种 骨髓基质细胞激活的信号通路靶基因的关键转录调控因子。BM 基质细胞诱导全基因组基因表达(转录组)和染色质重编程 MM细胞的可及性(调节组)，主要是由可溶性因子驱动的。综合分析 基因组结合数据表明C/eBPβ是骨髓基质细胞诱导的主要贡献者 转录组和调节组的转化。AS C/EBPβ过表达保护MM细胞 我们的初步结果将C/EBPβ定义为一个很有前途的新的研究课题 了解MM中新出现耐药性的表观遗传机制，我们假设 C/eBPβ通过转录调控参与可溶性因子介导的耐药 骨髓基质细胞激活促生长信号通路的靶基因