ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma.
ETV4-Dependent Transcriptional Plasticity Maintains MYC Expression and Results in IMiD Resistance in Multiple Myeloma.
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DOI：
10.1158/2643-3230.bcd-23-0061
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发表时间：
2024-01-08
影响因子：
11.2
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在对IMiD和Cereblon E3连接酶调节剂耐药的骨髓瘤细胞中，骨髓瘤增强子上ETV4的增加补偿了CUL4a-Cereblon对IKZF1和IKZF3的降解。免疫调节药物（IMiD）是多发性骨髓瘤（MM）的主要治疗方法。尽管它们有效，但大多数患者产生耐药性，其机制尚未完全确定。在这里，我们发现IMiD应答是由IKZF1和IKZF3的IMiD依赖性降解指导的，IKZF1和IKZF3结合维持MYC和其他骨髓瘤癌基因表达所必需的增强子。IMiD处理普遍减少染色质结合的IKZF1，但P300和BRD4共激活因子的清除仅发生在IMiD敏感细胞中。ikzf1结合的增强子与其他转录因子结合基序重叠，包括ETV4。染色质免疫沉淀测序显示，ETV4与IKZF1结合相同的增强子，ETV4 CRISPR/ cas9介导的消融导致IMiD耐药MM的增敏。ETV4的表达与细胞系中IMiD耐药、患者预后不良相关，并且在复发时上调。这些数据表明，ETV4通过维持致癌增强子活性来减轻MM对IKZF1和IKZF3的依赖性，并确定转录可塑性是一种以前未被认识的IMiD抗性机制。我们发现IKZF1结合的增强子对IMiD的疗效至关重要，并且因子ETV4可以结合相同的增强子并替代IKZF1，并通过维持MYC和其他癌基因介导IMiD耐药性。这些数据暗示转录因子冗余是MM中先前未被识别的IMiD耐药模式。参见Welsh， Barwick等人的相关文章，第34页。参见Yun和Cleveland的相关评论，第5页。本文载于《本期文章选集》第4页
In myeloma cells resistant to IMiD and Cereblon E3 ligase modulators, increased ETV4 at myeloma enhancers compensates for IKZF1 and IKZF3 degradation by CUL4a-Cereblon. Immunomodulatory drugs (IMiD) are a backbone therapy for multiple myeloma (MM). Despite their efficacy, most patients develop resistance, and the mechanisms are not fully defined. Here, we show that IMiD responses are directed by IMiD-dependent degradation of IKZF1 and IKZF3 that bind to enhancers necessary to sustain the expression of MYC and other myeloma oncogenes. IMiD treatment universally depleted chromatin-bound IKZF1, but eviction of P300 and BRD4 coactivators only occurred in IMiD-sensitive cells. IKZF1-bound enhancers overlapped other transcription factor binding motifs, including ETV4. Chromatin immunoprecipitation sequencing showed that ETV4 bound to the same enhancers as IKZF1, and ETV4 CRISPR/Cas9-mediated ablation resulted in sensitization of IMiD-resistant MM. ETV4 expression is associated with IMiD resistance in cell lines, poor prognosis in patients, and is upregulated at relapse. These data indicate that ETV4 alleviates IKZF1 and IKZF3 dependency in MM by maintaining oncogenic enhancer activity and identify transcriptional plasticity as a previously unrecognized mechanism of IMiD resistance. We show that IKZF1-bound enhancers are critical for IMiD efficacy and that the factor ETV4 can bind the same enhancers and substitute for IKZF1 and mediate IMiD resistance by maintaining MYC and other oncogenes. These data implicate transcription factor redundancy as a previously unrecognized mode of IMiD resistance in MM. See related article by Welsh, Barwick, et al., p. 34. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4