Han Cuijuan, Zhang Zhiping, Crosse Edie I, Sajedi Sogand, Lu Bin, Wang Xiyue, Karma Sadik, Kostich Mitch, Rajendran Sakthi Harini, Udy Dylan B, Chen Steven, Arnuk Alexander, Lawal Abimbola Eunice, Koenig Kayla R, McKenna Meryl, Reville Patrick K, Abbas Hussein A, Abdel-Wahab Omar, Miura Pedro, Bradley Robert K, Wang Eric
The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
Department of Genetics and Genome Sciences, UConn Health, Farmington, Connecticut.
Blood Cancer Discov. 2025 Sep 3;6(5):464-483. doi: 10.1158/2643-3230.BCD-24-0327.
Aberrant levels or structures of RNA isoforms are a hallmark of many cancers, including acute myeloid leukemia (AML), yet their role in AML chemoresistance remains unclear. We conducted a paired analysis of RNA isoform changes in patients with AML before therapy and at relapse after chemotherapy and identified intragenic DNA methylation at the proximal promoter of the transcription factor RUNX1, which resulted in elevated expression of the long-isoform RUNX1C through its alternative distal promoter. The unique N-terminal region of RUNX1C orchestrated an isoform-specific transcriptional program that promoted chemoresistance, with its direct target BTG2 playing a role in chemotherapy resistance. BTG2 promoted rRNA deadenylation, resulting in decreased mRNA expression and stability. Deletion of rRNAs increased cellular quiescence. Moreover, RNA-based targeting of RUNX1C reactivated quiescent leukemia cells and enhanced chemotherapy efficacy. These findings delineated an isoform-specific transcriptional circuit that governed chemotherapy response, providing a potential therapeutic strategy to mitigate AML recurrence.
This study identifies RUNX1C as a contributor to AML chemoresistance and an inducer of quiescence through BTG2. Targeting RUNX1C with RNA-based approaches disrupts this state and improves chemotherapy response, highlighting RUNX1C inhibition as a promising strategy to overcome resistance and enhance treatment efficacy in AML.
RNA异构体的异常水平或结构是包括急性髓性白血病（AML）在内的许多癌症的标志，但其在AML化疗耐药中的作用仍不清楚。我们对AML患者治疗前和化疗复发时的RNA异构体变化进行了配对分析，确定了转录因子RUNX1近端启动子处的基因内DNA甲基化，这通过其替代远端启动子导致长异构体RUNX1C表达升高。RUNX1C独特的N端区域精心编排了一个异构体特异性转录程序，促进化疗耐药，其直接靶点BTG2在化疗耐药中发挥作用。BTG2促进rRNA去腺苷酸化，导致mRNA表达和稳定性降低。rRNA的缺失增加了细胞静止。此外，基于RNA的RUNX1C靶向重新激活了静止的白血病细胞并增强了化疗疗效。这些发现描绘了一个控制化疗反应的异构体特异性转录回路，为减轻AML复发提供了一种潜在的治疗策略。
本研究确定RUNX1C是AML化疗耐药的促成因素，也是通过BTG2诱导静止的因素。用基于RNA的方法靶向RUNX1C可破坏这种状态并改善化疗反应，突出了抑制RUNX1C作为克服AML耐药和提高治疗疗效的一种有前景的策略。
