Rodriguez-Zabala M, Ramakrishnan R, Reinbach K, Ghosh S, Oburoglu L, Falqués-Costa A, Bellamkonda K, Ehinger M, Peña-Martínez P, Puente-Moncada N, Lilljebjörn H, Cammenga J, Pronk CJ, Lazarevic V, Fioretos T, Hagström-Andersson A, Woods NB, Järås M
Blood Adv - (-) - [2023-07-28; online 2023-07-28]
Acute myeloid leukemia (AML) is initiated and propagated by leukemia stem cells (LSCs), a self-renewing population of leukemia cells responsible for therapy resistance. Hence, there is an urgent need to identify new therapeutic opportunities targeting LSCs. Here we performed an in vivo CRISPR knockout screen to identify potential therapeutic targets by interrogating cell surface dependencies of LSCs. The facilitated glucose transporter type 1 (GLUT1) emerged as a critical in vivo metabolic dependency for LSCs in a murine MLL::AF9-driven model of AML. GLUT1 disruption by genetic ablation or pharmacological inhibition led to suppression of leukemia progression and improved survival of mice transplanted with LSCs. Metabolic profiling revealed that Glut1 inhibition suppressed glycolysis, decreased levels of tricarboxylic acid (TCA) cycle intermediates, and increased the levels of amino acids. This metabolic reprogramming was accompanied by an increase in autophagic activity and apoptosis. Moreover, Glut1 disruption caused transcriptional, morphological and immunophenotypic changes consistent with differentiation of AML cells. Notably, dual inhibition of GLUT1 and oxidative phosphorylation (OXPHOS) exhibited synergistic anti-leukemic effects in the majority of primary AML patient samples tested by restraining their metabolic plasticity. In particular, RUNX1-mutated primary leukemia cells displayed striking sensitivity to the combination treatment compared to normal CD34+ bone marrow and cord blood cells. Collectively, our study reveals a GLUT1 dependency of murine LSCs in the bone marrow microenvironment, and demonstrates that dual inhibition of GLUT1 and OXPHOS is a promising therapeutic approach for AML.