Details

Autor(en) / Beteiligte

• Rodriguez-Zabala, Maria
• Ramakrishnan, Ramprasad
• Reinbach, Katrin
• Ghosh, Somadri
• Oburoglu, Leal
• Falqués-Costa, Antoni
• Bellamkonda, Kishan
• Ehinger, Mats
• Peña-Martínez, Pablo
• Puente-Moncada, Noelia
• Lilljebjörn, Henrik
• Cammenga, Jörg
• Pronk, Cornelis Jan
• Lazarevic, Vladimir
• Fioretos, Thoas
• Hagström-Andersson, Anna K.
• Woods, Niels-Bjarne
• Järås, Marcus

Titel

Combined GLUT1 and OXPHOS inhibition eliminates acute myeloid leukemia cells by restraining their metabolic plasticity

Ist Teil von

• Blood advances, 2023-09, Vol.7 (18), p.5382-5395

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2023

Quelle

Alma/SFX Local Collection

Beschreibungen/Notizen

• •GLUT1 is essential for energy metabolism of murine MLL::AF9 LSCs in the bone marrow microenvironment.•GLUT1 and OXPHOS inhibition eliminates human AML cells. [Display omitted] 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 that received transplantation with LSCs. Metabolic profiling revealed that Glut1 inhibition suppressed glycolysis, decreased levels of tricarboxylic acid 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 antileukemic effects in the majority of tested primary AML patient samples through restraining of their metabolic plasticity. In particular, RUNX1-mutated primary leukemia cells displayed striking sensitivity to the combination treatment compared with 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.