Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma.
Chromatin-based, in cis and in trans regulatory rewiring underpins distinct oncogenic transcriptomes in multiple myeloma.
复制标题
DOI：
10.1038/s41467-021-25704-2
复制
发表时间：
2021-09-14
影响因子：
16.6
通讯作者：
Karadimitris A
中科院分区：
文献类型：
--
作者：
Alvarez-Benayas J;Trasanidis N;Katsarou A;Ponnusamy K;Chaidos A;May PC;Xiao X;Bua M;Atta M;Roberts IAG;Auner HW;Hatjiharissi E;Papaioannou M;Caputo VS;Sudbery IM;Karadimitris A
多发性骨髓瘤是骨髓浆细胞（PC）的遗传异质性癌症。不同的骨髓瘤转录组谱主要由骨髓瘤起始事件（MIE）驱动，并汇聚成CCND1和CCND2癌基因的互斥过表达。在这里，参考他们的正常同行，我们发现，骨髓瘤PC增强染色质可及性结合配对转录组分析可以分类MIE定义的遗传亚组。在不同的MM遗传亚组之间和内部，我们将骨髓瘤生物学关键基因和途径的调节归因于独特或共享的、发育激活的或从头形成的候选增强子。这种增强子共同招募现有的转录因子，虽然本身没有转录失调，但组织异常的基因调控网络，有助于识别具有预后影响的骨髓瘤细胞依赖性。最后，我们确定并验证了在MM和慢性淋巴细胞白血病患者亚组中调节CCND2异位表达的关键超级增强子。尽管存在广泛的遗传异质性，但近一半的多发性骨髓瘤（MM）病例是由细胞周期蛋白D2（CCND2）过表达引起的。在这里，作者剖析了MM的染色质景观，以提供对驱动MM的转录调控景观和对应于不同MM遗传亚型的不同转录组的见解。
Multiple myeloma is a genetically heterogeneous cancer of the bone marrow plasma cells (PC). Distinct myeloma transcriptome profiles are primarily driven by myeloma initiating events (MIE) and converge into a mutually exclusive overexpression of the CCND1 and CCND2 oncogenes. Here, with reference to their normal counterparts, we find that myeloma PC enhanced chromatin accessibility combined with paired transcriptome profiling can classify MIE-defined genetic subgroups. Across and within different MM genetic subgroups, we ascribe regulation of genes and pathways critical for myeloma biology to unique or shared, developmentally activated or de novo formed candidate enhancers. Such enhancers co-opt recruitment of existing transcription factors, which although not transcriptionally deregulated per se, organise aberrant gene regulatory networks that help identify myeloma cell dependencies with prognostic impact. Finally, we identify and validate the critical super-enhancer that regulates ectopic expression of CCND2 in a subset of patients with MM and in chronic lymphocytic leukemia. Despite extensive genetic heterogeneity, nearly half of all multiple myeloma (MM) cases are driven by cyclin D2 (CCND2) over-expression. Here the authors dissect the chromatin landscape of MM to provide insights into the transcriptional regulatory landscape driving MM and divergent transcriptomes corresponding to different MM genetic subtypes.
登录
查看更多内容
影响因子：
5.8
作者：
Liberzon, Arthur;Subramanian, Aravind;Mesirov, Jill P.
通讯作者：
Mesirov, Jill P.
影响因子：
14.9
作者：
Kuleshov MV;Jones MR;Rouillard AD;Fernandez NF;Duan Q;Wang Z;Koplev S;Jenkins SL;Jagodnik KM;Lachmann A;McDermott MG;Monteiro CD;Gundersen GW;Ma'ayan A
通讯作者：
Ma'ayan A
影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
影响因子：
11.1
作者：
Rampa C;Tian E;Våtsveen TK;Buene G;Slørdahl TS;Børset M;Waage A;Sundan A
通讯作者：
Sundan A
影响因子：
20.3
作者：
Annunziata, Christina M.;Hernandez, Lidia;Staudt, Louis M.
通讯作者：
Staudt, Louis M.