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

• Published in: Cell reports (Cambridge) Vol. 43; no. 2; p. 113704
• Main Authors: Rivera, Maria, Zhang, Haoran, Pham, Jessica, Isquith, Jane, Zhou, Qingchen Jenny, Balaian, Larisa, Sasik, Roman, Enlund, Sabina, Mark, Adam, Ma, Wenxue, Holm, Frida, Fisch, Kathleen M., Kuo, Dennis John, Jamieson, Catriona, Jiang, Qingfei
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.02.2024; Elsevier
• Subjects: CP: Cancer; CP: Immunology; epitranscriptome; leukemia-initiating cells; Medicin och hälsovetenskap; pediatric leukemia; RNA editing; CP: Immunology; leukemia-initiating cells; RNA editing; epitranscriptome; pediatric leukemia; CP: Cancer
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.113704

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. [Display omitted] •Elevated A-to-I RNA modifications are associated with increased risk of relapse•Loss of ADAR1 impairs LIC self-renewal partly via ADAR1-MDA5 axis•Cell-intrinsic level of MDA5 dictates the dependence of LICs on ADAR1-MDA5 axis•RNA-editing-independent activity suppresses ISGs Rivera et al. showed that widespread adenosine-to-inosine RNA editing by the RNA-editing enzyme ADAR1 is associated with leukemia relapse in patients with T-ALL. ADAR1 promotes LIC stemness via regulation of stem cell gene expression and suppression of MDA5-directed dsRNA sensing by RNA hyper-editing and RNA-editing-independent mechanisms.