Combined GLUT1 and OXPHOS inhibition eliminates acute myeloid leukemia cells by restraining their metabolic plasticity
(2023) In Blood Advances 7(18). p.5382-5395- Abstract
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.... (More)
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.
(Less)
- author
- organization
-
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- LUCC: Lund University Cancer Centre
- Targeted therapies in leukemia (research group)
- Hematopoietic Stem Cell Development (research group)
- Pathology, Lund
- Division of Clinical Genetics
- Translational Genomic and Functional Studies of Leukemia (research group)
- LTH Profile Area: Engineering Health
- The pathogenetic mechanisms behind MLL-rearranged acute leukemia in infancy (research group)
- publishing date
- 2023-09-26
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Blood Advances
- volume
- 7
- issue
- 18
- pages
- 5382 - 5395
- publisher
- American Society of Hematology
- external identifiers
-
- pmid:37505194
- scopus:85173448761
- ISSN
- 2473-9529
- DOI
- 10.1182/bloodadvances.2023009967
- language
- English
- LU publication?
- yes
- additional info
- Publisher Copyright: © 2023 by The American Society of Hematology.
- id
- 538bc163-463c-483d-acbd-781714e40337
- date added to LUP
- 2023-10-24 22:21:15
- date last changed
- 2025-02-08 08:33:59
@article{538bc163-463c-483d-acbd-781714e40337, abstract = {{<p>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<sup>+</sup> 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.</p>}}, author = {{Rodriguez-Zabala, Maria and Ramakrishnan, Ramprasad and Reinbach, Katrin and Ghosh, Somadri and Oburoglu, Leal and Falqués-Costa, Antoni and Bellamkonda, Kishan and Ehinger, Mats and Peña-Martínez, Pablo and Puente-Moncada, Noelia and Lilljebjörn, Henrik and Cammenga, Jörg and Pronk, Cornelis Jan and Lazarevic, Vladimir and Fioretos, Thoas and Hagström-Andersson, Anna K. and Woods, Niels Bjarne and Järås, Marcus}}, issn = {{2473-9529}}, language = {{eng}}, month = {{09}}, number = {{18}}, pages = {{5382--5395}}, publisher = {{American Society of Hematology}}, series = {{Blood Advances}}, title = {{Combined GLUT1 and OXPHOS inhibition eliminates acute myeloid leukemia cells by restraining their metabolic plasticity}}, url = {{http://dx.doi.org/10.1182/bloodadvances.2023009967}}, doi = {{10.1182/bloodadvances.2023009967}}, volume = {{7}}, year = {{2023}}, }