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. 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 editing is a common attribute of relapsed T cell acute lymphoblastic leukemia (T -ALL) regardless of molecular subtype. Consequently, knockdown of ADAR1 severely inhibits LIC self -renewal capacity and prolongs survival in T -ALL patient -derived xenograft models. Mechanistically, ADAR1 directs hyper -editing of immunogenic dsRNA to avoid detection by the innate immune sensor melanoma differentiation -associated protein 5 (MDA5). Moreover, we uncover that the cell -intrinsic level of MDA5 dictates the dependency on the 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.