Arnie Charbonneau Cancer Institute, University of Calgary, Calgary, -Canada.
Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.
Blood Cancer Discov. 2024 Jan 8;5(1):56-73. doi: 10.1158/2643-3230.BCD-23-0061.
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.
免疫调节药物（IMiD）是多发性骨髓瘤（MM）的主要治疗方法。尽管它们具有疗效，但大多数患者都会产生耐药性，其机制尚未完全确定。在这里，我们表明，IMiD 反应是由 IKZF1 和 IKZF3 的 IMiD 依赖性降解所指导的，这些蛋白与增强子结合，这些增强子对于维持 MYC 和其他骨髓瘤癌基因的表达是必要的。IMiD 治疗普遍耗尽了染色质结合的 IKZF1，但只有在 IMiD 敏感的细胞中才会驱逐 P300 和 BRD4 共激活因子。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 结合的增强子相同，并且 ETV4 CRISPR/Cas9 介导的消融导致 IMiD 耐药 MM 的敏感性增加。ETV4 的表达与细胞系中的 IMiD 耐药性、患者的预后不良以及复发时的上调有关。这些数据表明，ETV4 通过维持致癌增强子活性来减轻 MM 中 IKZF1 和 IKZF3 的依赖性，并确定转录可塑性为 IMiD 耐药的一种先前未被认识的机制。
我们表明，IKZF1 结合的增强子对于 IMiD 的疗效至关重要，并且因子 ETV4 可以结合相同的增强子，并通过维持 MYC 和其他癌基因来替代 IKZF1 并介导 IMiD 耐药。这些数据表明转录因子冗余是 MM 中 IMiD 耐药的一种先前未被认识的模式。请参阅 Welsh、Barwick 等人在本期的相关文章，第 34 页。请参阅 Yun 和 Cleveland 的相关评论，第 5 页。本文选自本期精选文章，第 4 页。
