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Thoas Fioretos

Thoas Fioretos

Research team manager

Thoas Fioretos

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

Author

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

Summary, in English

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.

Department/s

  • StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
  • LUCC: Lund University Cancer Centre
  • Targeted therapies in leukemia
  • Hematopoietic Stem Cell Development
  • Pathology, Lund
  • Division of Clinical Genetics
  • Translational Genomic and Functional Studies of Leukemia
  • LTH Profile Area: Engineering Health
  • The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy

Publishing year

2023-09-26

Language

English

Pages

5382-5395

Publication/Series

Blood Advances

Volume

7

Issue

18

Document type

Journal article

Publisher

American Society of Hematology

Topic

  • Hematology
  • Cell and Molecular Biology

Status

Published

Research group

  • Targeted therapies in leukemia
  • Hematopoietic Stem Cell Development
  • Translational Genomic and Functional Studies of Leukemia
  • The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy

ISBN/ISSN/Other

  • ISSN: 2473-9529