Transcriptional Heterogeneity Overcomes Super-Enhancer Disrupting Drug Combinations in Multiple Myeloma.

IF 11.5 Q1 HEMATOLOGY
Seth J Welsh, Benjamin G Barwick, Erin W Meermeier, Daniel L Riggs, Chang-Xin Shi, Yuan Xiao Zhu, Meaghen E Sharik, Megan T Du, Leslie D Abrego Rocha, Victoria M Garbitt, Caleb K Stein, Joachim L Petit, Nathalie Meurice, Yuliza Tafoya Alvarado, Rodrigo Fonseca, Kennedi T Todd, Sochilt Brown, Zachery J Hammond, Nicklus H Cuc, Courtney Wittenberg, Camille Herzog, Anna V Roschke, Yulia N Demchenko, Wei-Dong D Chen, Peng Li, Wei Liao, Warren J Leonard, Sagar Lonial, Nizar J Bahlis, Paola Neri, Lawrence H Boise, Marta Chesi, P Leif Bergsagel
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Abstract

Multiple myeloma (MM) is a malignancy that is often driven by MYC and that is sustained by IRF4, which are upregulated by super-enhancers. IKZF1 and IKZF3 bind to super-enhancers and can be degraded using immunomodulatory imide drugs (IMiD). Successful IMiD responses downregulate MYC and IRF4; however, this fails in IMiD-resistant cells. MYC and IRF4 downregulation can also be achieved in IMiD-resistant tumors using inhibitors of BET and EP300 transcriptional coactivator proteins; however, in vivo these drugs have a narrow therapeutic window. By combining IMiDs with EP300 inhibition, we demonstrate greater downregulation of MYC and IRF4, synergistic killing of myeloma in vitro and in vivo, and an increased therapeutic window. Interestingly, this potent combination failed where MYC and IRF4 expression was maintained by high levels of the AP-1 factor BATF. Our results identify an effective drug combination and a previously unrecognized mechanism of IMiD resistance.

Significance: These results highlight the dependence of MM on IKZF1-bound super-enhancers, which can be effectively targeted by a potent therapeutic combination pairing IMiD-mediated degradation of IKZF1 and IKZF3 with EP300 inhibition. They also identify AP-1 factors as an unrecognized mechanism of IMiD resistance in MM. See related article by Neri, Barwick, et al., p. 56. See related commentary by Yun and Cleveland, p. 5. This article is featured in Selected Articles from This Issue, p. 4.

转录异质性克服了多发性骨髓瘤中破坏超级增强子的药物组合。
多发性骨髓瘤(MM)是一种恶性肿瘤,通常由MYC驱动,并由超级增强子上调的IRF4维持。IKZF1和IKZF3与超级增强子结合,并可使用免疫调节酰亚胺药物(IMiDs)降解。成功的IMiD反应下调MYC和IRF4;然而,这在IMiD抗性细胞中失败。MYC和IRF4的下调也可以在IMiD抗性肿瘤中使用BET和EP300转录共激活蛋白的抑制剂来实现;然而,在体内,这些药物的治疗窗口很窄。通过将IMiDs与EP300抑制相结合,我们证明了MYC和IRF4的下调更大,在体外和体内协同杀伤骨髓瘤,并增加了治疗窗口。有趣的是,这种有效的组合失败了,MYC和IRF4的表达是由高水平的AP-1因子BATF维持的。我们的研究结果确定了一种有效的药物组合和一种以前未被认识的IMiD耐药性机制。
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
CiteScore
12.70
自引率
1.80%
发文量
139
期刊介绍: The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.
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