Malignant A-to-I RNA editing by ADAR1 drives T-cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing

Leukemia initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Identifying direct stemness determinants that fuel LIC self-renewal is critical for developing targeted approaches to eliminate LICs and prevent relapse. Here, we show that the RNA editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant double-stranded RNA (dsRNA) sensing. Elevated adenosine-to-inosine (A-to-I) editing is a common attribute of relapsed T-ALL regardless of molecular subtypes. Consequently, knockdown of ADAR1 severely inhibits LIC self-renewal capacity and prolongs survival in T-ALL PDX models. Mechanistically, ADAR1 directs hyper-editing of immunogenic dsRNA to avoid detection by the innate immune sensor MDA5. Moreover, we uncovered that the cell intrinsic level of MDA5 dictates the dependency on ADAR1-MDA5 axis in T-ALL. Collectively, our results show that ADAR1 functions as a self-renewal factor that limits the sensing of endogenous dsRNA. Thus, targeting ADAR1 presents an effective therapeutic strategy for eliminating T-ALL LICs. Comparative gene expression profiling analysis of RNA-seq data for T-ALL patient samples following ADAR1 knockdown by shRNA.

白血病起始细胞（Leukemia initiating cells, LICs）被认为是白血病复发与治疗抵抗的根源。鉴定驱动白血病起始细胞自我更新的直接干性决定因子，对于开发靶向清除白血病起始细胞、预防白血病复发的治疗策略至关重要。本研究发现，RNA编辑酶ADAR1是一种关键的干性因子，可通过减弱异常双链RNA（double-stranded RNA, dsRNA）的感知信号来促进白血病起始细胞的自我更新。腺苷-肌苷（adenosine-to-inosine, A-to-I）编辑水平升高是复发性T细胞急性淋巴细胞白血病（T-ALL）的常见特征，无论其分子亚型如何。研究结果显示，敲低ADAR1可显著抑制白血病起始细胞的自我更新能力，并延长T细胞急性淋巴细胞白血病患者来源异种移植（patient-derived xenograft, PDX）模型的宿主生存期。从机制层面而言，ADAR1可指导免疫原性双链RNA发生超编辑，从而避免被先天免疫传感器MDA5识别。此外，本研究还发现，细胞内源性MDA5水平决定了T细胞急性淋巴细胞白血病对ADAR1-MDA5信号轴的依赖性。综上，本研究结果表明，ADAR1作为一种自我更新因子，可限制内源性双链RNA的感知信号。因此，靶向ADAR1是一种清除T细胞急性淋巴细胞白血病白血病起始细胞的有效治疗策略。本研究针对经短发卡RNA（short hairpin RNA, shRNA）敲低ADAR1后的T细胞急性淋巴细胞白血病患者样本的RNA测序（RNA-seq）数据开展了比较基因表达谱分析。