Malignant A-to-I RNA editing by ADAR1 drives T cell acute lymphoblastic leukemia relapse via attenuating dsRNA sensing
Maria Rivera,
Haoran Zhang,
Jessica Pham,
Jane Isquith,
Qingchen Jenny Zhou,
Larisa Balaian,
Roman Sasik,
Sabina Enlund,
Adam Mark,
Wenxue Ma,
Frida Holm,
Kathleen M. Fisch,
Dennis John Kuo,
Catriona Jamieson,
Qingfei Jiang
Affiliations
Maria Rivera
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
Haoran Zhang
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
Jessica Pham
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Jane Isquith
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Qingchen Jenny Zhou
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
Larisa Balaian
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Roman Sasik
Center for Computational Biology & Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92093-0681, USA
Sabina Enlund
Department of Women’s and Children’s Health, Division of Pediatric Oncology and Pediatric Surgery, Karolinska Institutet, Solna, Sweden
Adam Mark
Center for Computational Biology & Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92093-0681, USA
Wenxue Ma
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
Frida Holm
Department of Women’s and Children’s Health, Division of Pediatric Oncology and Pediatric Surgery, Karolinska Institutet, Solna, Sweden
Kathleen M. Fisch
Center for Computational Biology & Bioinformatics (CCBB), University of California, San Diego, La Jolla, CA 92093-0681, USA; Department of Obstetrics, Gynecology & Reproductive Sciences, University of California, San Diego, La Jolla, CA 92037, USA
Dennis John Kuo
Moores Cancer Center, La Jolla, CA 92037, USA; Division of Pediatric Hematology-Oncology, Rady Children’s Hospital San Diego, University of California, San Diego, San Diego, CA 92123, USA
Catriona Jamieson
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA
Qingfei Jiang
Division of Regenerative Medicine, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Moores Cancer Center, La Jolla, CA 92037, USA; Corresponding author
Summary: 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.
