Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma.
Bone Marrow Stroma-Induced Transcriptome and Regulome Signatures of Multiple Myeloma.
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骨髓基质诱导的多发性骨髓瘤的转录组和调节剂特征。
DOI：
10.3390/cancers14040927
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发表时间：
2022-02-13
期刊：
影响因子：
5.2
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Dziadowicz SA;Wang L;Akhter H;Aesoph D;Sharma T;Adjeroh DA;Hazlehurst LA;Hu G
骨髓（BM）微环境为多发性骨髓瘤（MM）提供了抗治疗药物的保护性避难所。MM细胞与BM基质细胞（BMSC）相互作用，这种相互作用足以赋予从头多药耐药性与表观遗传机制，作为尚未阐明的贡献者之一。我们分析了MM细胞与BMSC相互作用的基因表达（转录组）和染色质可及性（调节组）的全基因组景观，并表征了诱导的特征。我们评估了来自BMSC的可溶性因子的贡献，并将这些结果与BMSC诱导的转录组和调节组变化的物理粘附进行了比较。多组学方法进一步确定了通过调节调节组来调节BMSC诱导的转录组的候选转录因子，这可能导致有希望的用于治疗MM的新的治疗靶点。多发性骨髓瘤（MM）是具有不可避免的耐药性的血液系统癌症。MM细胞与骨髓基质细胞（BMSC）相互作用，在转录组中发生实质性变化，并重新产生多药耐药性。作为转录调控的关键组成部分，染色质景观如何在暴露于BMSC的MM细胞中转化并有助于对BMSC的转录应答仍然是难以捉摸的。我们使用transwell共培养系统与BMSC分析了MM细胞的转录组和调节组。来自上部transwell的MM细胞的转录组和调节组类似于与来自下部腔室的BMSC共存的MM细胞，但与单一培养物不同。BMSC诱导的基因在JAK 2/STAT 3信号通路、未折叠蛋白应激、早期浆细胞的特征和对蛋白酶体抑制剂的反应中富集。在多个调控位点具有增加的可及性的基因优先被BMSCs诱导;这些基因富集与药物反应和不利的临床结果相关的功能。我们提出JUNB和ATF 4：：CEBPβ作为候选转录因子（TF），其调节与转录反应相关的调节组的BMSC诱导的转化。总之，我们表征了骨髓基质细胞诱导的MM细胞的转录组和调节组特征，以促进骨髓基质细胞诱导的MM多药耐药的表观遗传机制的研究。
The bone marrow (BM) microenvironment provides a protective sanctuary for multiple myeloma (MM) against therapeutic agents. MM cells interact with BM stromal cells (BMSCs) and the interaction is sufficient to confer de novo multi-drug resistance with epigenetic mechanisms as one of the contributors yet to be elucidated. We profiled genome-wide landscapes of gene expression (transcriptome) and chromatin accessibility (regulome) for MM cells interacting with BMSCs and characterized the induced signatures. We evaluated the contributions from soluble factors derived from BMSCs and compared these results to physical adhesion to the BMSC-induced changes in the transcriptome and regulome. The multi-omics approach further identified candidate transcription factors that regulate the BMSC-induced transcriptome through modulating the regulome, which may lead to promising novel therapeutic targets for the treatment of MM. Multiple myeloma (MM) is a hematological cancer with inevitable drug resistance. MM cells interacting with bone marrow stromal cells (BMSCs) undergo substantial changes in the transcriptome and develop de novo multi-drug resistance. As a critical component in transcriptional regulation, how the chromatin landscape is transformed in MM cells exposed to BMSCs and contributes to the transcriptional response to BMSCs remains elusive. We profiled the transcriptome and regulome for MM cells using a transwell coculture system with BMSCs. The transcriptome and regulome of MM cells from the upper transwell resembled MM cells that coexisted with BMSCs from the lower chamber but were distinctive to monoculture. BMSC-induced genes were enriched in the JAK2/STAT3 signaling pathway, unfolded protein stress, signatures of early plasma cells, and response to proteasome inhibitors. Genes with increasing accessibility at multiple regulatory sites were preferentially induced by BMSCs; these genes were enriched in functions linked to responses to drugs and unfavorable clinic outcomes. We proposed JUNB and ATF4::CEBPβ as candidate transcription factors (TFs) that modulate the BMSC-induced transformation of the regulome linked to the transcriptional response. Together, we characterized the BMSC-induced transcriptome and regulome signatures of MM cells to facilitate research on epigenetic mechanisms of BMSC-induced multi-drug resistance in MM.
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DOI：
10.1093/bioinformatics/btr064
发表时间：
2011-04-01
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Grant CE;Bailey TL;Noble WS
通讯作者：
Noble WS
影响因子：
11.4
作者：
Fan F;Malvestiti S;Vallet S;Lind J;Garcia-Manteiga JM;Morelli E;Jiang Q;Seckinger A;Hose D;Goldschmidt H;Stadlbauer A;Sun C;Mei H;Pecherstorfer M;Bakiri L;Wagner EF;Tonon G;Sattler M;Hu Y;Tassone P;Jaeger D;Podar K
通讯作者：
Podar K
DOI：
10.1016/j.neo.2021.11.009
发表时间：
2022-01
期刊：
Neoplasia (New York, N.Y.)
影响因子：
--
作者：
Bennett MK;Li M;Tea MN;Pitman MR;Toubia J;Wang PP;Anderson D;Creek DJ;Orlowski RZ;Gliddon BL;Powell JA;Wallington-Beddoe CT;Pitson SM
通讯作者：
Pitson SM
影响因子：
11.4
作者：
Fan, F.;Bashari, M. H.;Podar, K.
通讯作者：
Podar, K.
影响因子：
14.9
作者：
Bailey TL;Johnson J;Grant CE;Noble WS
通讯作者：
Noble WS