Selective Enhancer Gain of Function Deregulates MYC Expression in Multiple Myeloma.

IF 12.5 1区 医学 Q1 ONCOLOGY
Mahshid Rahmat, Kendell Clement, Jean-Baptiste Alberge, Romanos Sklavenitis-Pistofidis, Rohan Kodgule, Charles P Fulco, Daniel Heilpern-Mallory, Katarina Nilsson, David Dorfman, Jesse M Engreitz, Gad Getz, Luca Pinello, Russell Ryan, Irene M Ghobrial
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引用次数: 0

Abstract

MYC deregulation occurs in the majority of multiple myeloma (MM) cases and is associated with progression and worse prognosis. Enhanced MYC expression occurs in about 70% of MM patients, but it is known to be driven by translocation or amplification events in only ~40% of myelomas. Here, we used CRISPR interference (CRISPRi) to uncover an epigenetic mechanism of MYC regulation whereby increased accessibility of a plasma cell-type specific enhancer leads to increased MYC expression. This native enhancer activity was not associated with enhancer hijacking events but led to specific binding of c-MAF, IRF4, and SPIB transcription factors that activated MYC expression in the absence of known genetic aberrations. In addition, focal amplification was another mechanism of activation of this enhancer in approximately 3.4% of MM patients. Together, these findings define an epigenetic mechanism of MYC deregulation in MM beyond known translocations or amplifications and point to the importance of non-coding regulatory elements and their associated transcription factor networks as drivers of MM progression.

选择性增强子功能增益可解除多发性骨髓瘤中 MYC 的表达。
MYC失调发生在大多数多发性骨髓瘤(MM)病例中,与病情进展和预后恶化有关。约70%的MM患者会出现MYC表达增强,但已知只有约40%的骨髓瘤是由易位或扩增事件驱动的。在这里,我们利用CRISPR干扰(CRISPRi)发现了MYC调控的表观遗传学机制,即浆细胞型特异性增强子的可及性增加导致MYC表达增加。这种原生增强子活性与增强子劫持事件无关,但会导致 c-MAF、IRF4 和 SPIB 转录因子的特异性结合,从而在没有已知基因畸变的情况下激活 MYC 的表达。此外,在约 3.4% 的 MM 患者中,病灶扩增是激活该增强子的另一种机制。这些发现共同确定了MM中MYC失调的表观遗传学机制,而不是已知的易位或扩增,并指出了非编码调控元件及其相关转录因子网络作为MM进展驱动因素的重要性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Cancer research
Cancer research 医学-肿瘤学
CiteScore
16.10
自引率
0.90%
发文量
7677
审稿时长
2.5 months
期刊介绍: Cancer Research, published by the American Association for Cancer Research (AACR), is a journal that focuses on impactful original studies, reviews, and opinion pieces relevant to the broad cancer research community. Manuscripts that present conceptual or technological advances leading to insights into cancer biology are particularly sought after. The journal also places emphasis on convergence science, which involves bridging multiple distinct areas of cancer research. With primary subsections including Cancer Biology, Cancer Immunology, Cancer Metabolism and Molecular Mechanisms, Translational Cancer Biology, Cancer Landscapes, and Convergence Science, Cancer Research has a comprehensive scope. It is published twice a month and has one volume per year, with a print ISSN of 0008-5472 and an online ISSN of 1538-7445. Cancer Research is abstracted and/or indexed in various databases and platforms, including BIOSIS Previews (R) Database, MEDLINE, Current Contents/Life Sciences, Current Contents/Clinical Medicine, Science Citation Index, Scopus, and Web of Science.
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