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: 10618417
• 负责人: Gangqing Hu
• 金额: $ 26.32万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-25 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10618417
• 关键词: EBPJ3; bone; marrow; stromal; cell

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 实验室的目的是了解骨血液系统癌症耐药性的表观遗传机制 骨髓微环境。我有超过12年的转录调控研究经验， 免疫细胞、胚胎干细胞和癌细胞中的染色质调节剂。这项提议是为了调查 亮氨酸拉链TF C/EBPβ在促进肿瘤细胞新生耐药中的转录调控作用 BM微环境中的多发性骨髓瘤（MM）。MM是由恶性浆B细胞引起的疾病 主要在骨髓中增殖。它是无法治愈的，主要是因为出现耐药性后， 治疗。对耐药性的一个重要贡献来自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， 成分如基质细胞和成骨细胞。新生耐药性的出现发生在 短的时间框架，是可逆的，这表明表观遗传机制作为一个重要的贡献者。 然而，染色质调节剂的身份和机制有助于从头耐药， 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作为一个 BM基质细胞激活的信号通路靶基因的关键转录调节因子。的BM 基质细胞诱导基因表达（转录组）和染色质的全基因组重编程 MM细胞的可接近性（调节组），结果主要由可溶性因子驱动。综合分析 ENCODE基因组结合数据表明，C/EBPβ是BM基质细胞诱导的 转录组和调节组的转化。由于C/EBPβ-过表达保护MM细胞免于 IMiD化合物，我们的初步结果确定C/EBPβ作为一个有前途的新的研究课题， 了解MM中出现新生耐药性的表观遗传机制。我们假设 C/EBPβ通过转录调节可溶性因子介导的耐药性， BM基质细胞通过激活促生长信号通路的靶基因