ADAR1 drives stemness of leukemia initiating cells in T-cell acute lymphoblastic leukemia via attenuating immunogenic dsRNA sensing

Abstract

Abstract Leukemia initiating cells (LICs) are regarded as the origin of leukemia relapse and therapeutic resistance. Since T-cell acute lymphoblastic leukemia (T-ALL) LICs share many of the same features as normal T-cell precursors, identifying direct stemness determinants is critical for developing targeted approaches to eliminate LICs while sparing normal thymopoiesis. Here, we show that activation of the RNA editing enzyme ADAR1 is a crucial stemness factor that promotes LIC self-renewal by attenuating aberrant interferon signaling. Mechanistically, ADAR1 directs adenosine-to-inosine (A-to-I) hyper-editing of immunogenic double-stranded RNA (dsRNA) and retains unedited nuclear dsRNA to avoid detection by the innate immune sensor MDA5. Moreover, dynamic activation of ADAR1 orchestrates early T-cell progenitor lineage commitment from hematopoietic stem cells. However, the gene regulatory program diverges significantly between normal and malignant cellular backgrounds. ADAR1 suppresses interferon stimulated genes in T-cell progenitors while promotes self-renewal gene program in T-ALL LICs. Inhibition of MATR3, a T-ALL LIC specific ADAR1 target, impairs leukemia growth and induces apoptosis. These results suggest that modulation of ADAR1 downstream targets present safe and effective therapeutic strategies for T-ALL LICs.