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

Rodriguez-Zabala, Maria LU ; Ramakrishnan, Ramprasad LU ; Reinbach, Katrin LU ; Ghosh, Somadri LU orcid ; Oburoglu, Leal LU orcid ; Falqués-Costa, Antoni ; Bellamkonda, Kishan LU ; Ehinger, Mats LU ; Peña-Martínez, Pablo LU and Puente-Moncada, Noelia LU , et al. (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.

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organization
publishing date
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
2024-04-19 02:52:18
@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}},
}