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

C/EBPβ 骨髓基质细胞介导的多发性骨髓瘤耐药性

• 批准号: 10709274
• 负责人: Gangqing Hu
• 金额: $ 23.78万
• 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 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10709274
• 关键词: Apoptosis; B-Lymphocytes; Binding; Binding Sites; Biological Process; Bone Marrow; Bone Marrow Neoplasms; CCAAT-Enhancer-Binding Protein-beta; Cell Line; Cell Proliferation; Cell Survival; Cells; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Coculture Techniques; Conditioned Culture Media; DNA Sequence Alteration; Data; Development; Diagnosis; Disease; Drug Compounding; Drug resistance; Engraftment; Enhancers; Epigenetic Process; Exhibits; Gene Expression; Gene Expression Profile; Genes; Genetic Transcription; Genome; Genomics; Goals; Growth; Hematologic Neoplasms; Human; IL6 gene; Immunologic Deficiency Syndromes; Knowledge; Laboratories; Leucine Zippers; Link; Malignant - descriptor; Malignant Neoplasms; Measures; Mediating; Modeling; Multi-Drug Resistance; Multiple Myeloma; Mus; Osteoblasts; Pathway interactions; Patients; Plasma; Play; Prognostic Marker; Repression; Residual Neoplasm; Resistance; Role; Signaling Protein; Site; Stromal Cells; Testing; Transcriptional Regulation; Treatment outcome; Tumor Burden; Work; XCL1 gene; chemotherapy; clinically significant; defined contribution; epigenetic regulation; genetic signature; genome-wide; genome-wide analysis; immune modulating agents; improved; in vivo; innovation; lenalidomide; method development; mouse model; multiple omics; novel strategies; novel therapeutic intervention; overexpression; pomalidomide; programs; protective effect; response; stem; transcription factor; transcriptome; transcriptome sequencing; tumor; tumor microenvironment

PROJECT SUMMARY – C/EBPβ in bone marrow stromal cell-mediated drug resistance of multiple myeloma 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 promoted by the bone marrow (BM) microenvironment. This proposal will investigate the transcriptional-regulatory role of a leucine-zipper transcription factor (TF) called CCAAT/enhancer-binding protein beta (C/EBPβ) in promoting de novo drug resistance of Multiple Myeloma (MM) in the context of the BM microenvironment. MM is a disease caused by malignant plasma B cells mainly residing in the BM. It is incurable largely because of the emergence of drug resistance. 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, osteoblasts, and matrices. The emergence of de novo drug resistance occurs in a short timeframe and is reversible, suggesting epigenetic mechanisms may be an important driver. However, the mechanisms of chromatin regulators contributing to de novo drug resistance of MM in the BM microenvironment remain largely unexplored. Our work predicted C/EBPβ as a key transcription regulator of target genes of signaling pathways activated by the BM stromal cells. The BM stromal cells induced a genome- wide reprogramming in gene expression (transcriptome) and chromatin accessibility (regulome) of MM cells, mainly driven by soluble factors. Integrative analysis with ENCODE genomic binding data indicated C/EBPβ as a major contributor to the BM stromal cell-induced transformation of transcriptome and regulome. Our preliminary results defined C/EBPβ as a promising subject to understand epigenetic mechanisms for the emergence of de novo drug resistance in MM. We hypothesize that C/EBPβ modulates chromatin accessibility for transcriptional regulation, and through which contributes to soluble factor-mediated drug resistance in MM cells. We will test this hypothesis from two directions. In AIM 1, we will first validate the growth-promoting role of C/EBPβ using CRISPR KO of CEBPB in MM cell lines combined with engraftment model in immunodeficient NSG mice. Then we will define soluble factor-induced signature genes regulated by C/EBPβ through an integrative analysis of genome-wide profiles of gene expression and accessible chromatin. In AIM 2, we will examine the impact of C/EBPβ loss on soluble factor-mediated drug resistance to IMiDs and define the underlying genome-wide transcription signatures linked to the resistance and regulated by C/EBPβ. Results from this proposal will establish whether targeting the C/EBPβ pathway is a rational method for the development of novel therapeutic strategies to suppress de novo drug resistance as promoted by the BM microenvironment for MM cells.

项目总结- C/EBPβ在骨髓基质细胞介导的多药耐药中的作用 骨髓瘤 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 该实验室的目的是了解血液系统癌症的耐药性的表观遗传机制， 骨髓微环境。这项提案将调查转录调控的作用， 亮氨酸拉链转录因子（TF），称为CCAAT/增强子结合蛋白β（C/EBPβ）， 多发性骨髓瘤（MM）在BM微环境中的新发耐药性。MM是一种疾病 由主要存在于BM中的恶性浆B细胞引起。它之所以无法治愈，主要是因为 抗药性的证据。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， 组分如基质细胞、成骨细胞和基质。新耐药的出现 在很短的时间内，并且是可逆的，这表明表观遗传机制可能是一个重要的驱动因素。然而，在这方面， 染色质调节因子导致骨髓中MM新生耐药性的机制 微环境在很大程度上尚未被探索。我们的工作预测C/EBPβ是一个关键的转录调节因子， BM基质细胞激活的信号通路的靶基因。骨髓基质细胞诱导了一个基因组- MM细胞的基因表达（转录组）和染色质可及性（调节组）的广泛重编程， 主要由可溶性因素驱动。与ENCODE基因组结合数据的综合分析表明C/EBPβ为 BM基质细胞诱导的转录组和调节组转化的主要贡献者。我们的初步 结果表明，C/EBPβ是一个很有前途的主题，以了解表观遗传机制的出现， 我们假设C/EBPβ调节MM的染色质可及性， 转录调控，并通过其有助于可溶性因子介导的耐药性， MM细胞。我们将从两个方面来检验这个假设。在AIM 1中，我们将首先验证 使用CEBPB的CRISPR KO的C/EBPβ在MM细胞系中的作用结合移植模型， 免疫缺陷NSG小鼠。在此基础上，我们将定义受C/EBPβ调控的可溶性因子诱导的标签基因 通过对全基因组基因表达谱和可及染色质的综合分析。在AIM 2中， 我们将研究C/EBPβ缺失对可溶性因子介导的IMiD耐药的影响，并确定 潜在的全基因组转录特征与抗性相关并受C/EBPβ调控。结果 该提案将确定靶向C/EBPβ通路是否是开发 新的治疗策略，以抑制从头耐药性，促进由BM微环境， MM细胞。