ArticleNature communications2022
Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic reprogramming in T-cell acute lymphoblastic leukemia.
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Article in Nature communications, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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48citing papers in PubMed
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Who cites it
48 citing papers in PubMed.
- Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.Nature cancer · 2024Trial
- Therapeutic activation of PPARα contributes to NOTCH1 inhibition in T-cell acute lymphoblastic leukemia.BMC medicine · 2026Article
- Mitochondrial integrated stress response activation creates a therapeutic vulnerability to MCL-1 inhibition in acute myeloid leukemia.Cell death & disease · 2026Article
- β3-adrenergic blockade targets fatty acid oxidation to induce ferroptotic vulnerability in pediatric T-ALL.Biology direct · 2026Article
- Mitochondria-targeted metformin analogs activate the ER stress-unfolded protein response pathway to drive apoptosis in pancreatic cancer.Cell death & disease · 2026Article
- Functional cooperation between the B-cell receptor and NOTCH1 in regulating metabolic reprogramming in chronic lymphocytic leukemia.Leukemia · 2026Article
- Article
- BCAA catabolism mediates POU2AF1 propionylation to enhance T-ALL development.Cellular oncology (Dordrecht, Netherlands) · 2026Article
- RGX-019-MMAE inhibits leukemia progression by targeting MER proto-oncogene tyrosine kinase (MERTK) in acute myeloid leukemia.Journal of experimental & clinical cancer research : CR · 2026Article
- Fueling the Fire: How Glutamine Metabolism Sustains Leukemia Growth and Resistance.BioMed (Basel, Switzerland) · 2026Article
- Mechanistic role of GNE-987 targeting BRD4-HCP5 axis in pediatric T-cell acute lymphoblastic leukemia.Journal of cell communication and signaling · 2026Article
- Proteomics landscape of early T-cell precursor acute lymphoblastic leukemia reveals deficient oxidative phosphorylation signatures.Cell reports. Medicine · 2026Article
- The mitochondria as an emerging target of self-renewal in T-cell acute lymphoblastic leukemia.Cancer biology & therapy · 2025Review
- Canagliflozin synergises with serine restriction mediating anti-leukaemic effects in T-cell acute lymphoblastic leukaemia.Molecular metabolism · 2025Article
- Targeting the IKZF1/BCL-2 axis as a novel therapeutic strategy for treating acute T-cell lymphoblastic leukemia.Cancer biology & therapy · 2025Article
- Targeting tumor metabolic flexibility enhances radiotherapeutic efficacy via mitochondrial complex I Inhibition in an intracranial S180 sarcoma mouse model.Scientific reports · 2025Article
- Immunometabolic reprogramming in lung cancer: interplay between immune and stem-like cells in immune checkpoint inhibitor resistance.Journal of translational medicine · 2025Review
- Targeting NOTCH1-KEAP1 axis retards chronic liver injury and liver cancer progression via regulating stabilization of NRF2.Journal of experimental & clinical cancer research : CR · 2025Article
- Dysregulation of Mitochondrial Function in Cancer Cells.International journal of molecular sciences · 2025Review
- Decoding the diagnostic biomarkers of mitochondrial dysfunction related gene variants in pediatric T cell acute lymphoblastic leukemia.Scientific reports · 2025Article
Corrections and comments
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Authors and funding
55 authors.
Natalia BaranDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0003-0618-4798
Alessia LodiDepartment of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
Yogesh DhunganaSt. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Shelley HerbrichDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Meghan CollinsDepartment of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.ORCID 0000-0002-6201-9298
Shannon SweeneyDepartment of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
Renu PandeyDepartment of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
Anna SkwarskaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Shraddha PatelDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mathieu TremblayInstitute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.
Vinitha Mary KuruvillaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Antonio CavazosDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Mecit KaplanDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0003-0079-8617
Marc O WarmoesDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Diogo Troggian VeigaThe Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
Ken FurudateDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0003-1272-5490
Shanti Rojas-SutterinInstitute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.
Andre HamanInstitute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.
Yves GareauInstitute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.
Anne MarinierInstitute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.ORCID 0000-0002-0116-8345
Helen MaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Karine HarutyunyanDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
May DaherDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Luciana Melo GarciaDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Gheath Al-AtrashDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sujan PiyaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-8976-540X
Vivian RuvoloDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Wentao YangDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.
Sriram Saravanan ShanmugavelandyDepartment of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Ningping FengTRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA.
Jason GayTRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA.
Di DuDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-8851-8466
Jun J YangDepartment of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0002-0770-9659
Fieke W HoffDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Marcin KaminskiDepartment of Immunology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0002-9026-0185
Katarzyna TomczakDepartment of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
R Eric DavisDepartment of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0001-7311-0065
Daniel HerranzRutgers Robert Wood Johnson Medical School, Cancer Institute of New Jersey, New Brunswick, NJ, USA.ORCID 0000-0003-1768-5969
Adolfo FerrandoIrving Cancer Research Center, Columbia University Irving Medical Center, New York, NY, USA.ORCID 0000-0002-6212-8574
Elias J JabbourDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
M Emilia Di FrancescoInstitute for Applied Cancer Science, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
David T TeacheyPerelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, USA.ORCID 0000-0001-7373-8987
Terzah M HortonTexas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.ORCID 0000-0001-8293-4242
Steven KornblauDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-5990-9548
Katayoun RezvaniDepartment of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Guy SauvageauInstitute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.
Mihai GageaDepartment of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-2399-1375
Michael AndreeffDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-1144-1958
Koichi TakahashiDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0002-8027-9659
Joseph R MarszalekTRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. Anderson Cancer Center, Houston, USA.
Philip L LorenziDepartment of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.ORCID 0000-0003-0385-7774
Jiyang YuDepartment of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, USA.ORCID 0000-0003-3629-4330
Stefano TizianiDepartment of Nutritional Sciences, Dell Pediatric Research Institute, Dell Medical School, The University of Texas at Austin, Austin, TX, USA.
Trang HoangInstitute for Research in Immunology and Cancer, The University of Montreal, Montréal, QC, Canada.
Marina KonoplevaDepartment of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. mkonople@mdanderson.org.ORCID 0000-0002-9347-2212
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Kathrin Milbury · 1985 to 2026
$290.8MUniversity of Texas M.D. Anderson Cancer SPORE-LeukemiaP50CA100632 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI DRAETTA, GIULIO FRANCESCO · 2003 to 2023
$43.7MMolecular pathways and targeted therapies in human leukemiaR35CA210065 · NCI · COLUMBIA UNIVERSITY HEALTH SCIENCES · PI FERRANDO, ADOLFO A. · 2017 to 2021
$4.7MTargeting mitochondrial complex I in acute lymphoblastic leukemiaR01CA231364 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI KONOPLEVA, MARINA Y · 2019 to 2024
$2.9MIntracellular and Intercellular Network Rewiring and Hidden Driver Inference from Single-Cell DataR01GM134382 · NIGMS · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · PI YU, JIYANG · 2019 to 2023
$1.7MOrbitrap Elite High-Resolution Mass Spectrometer for Proteomics and MetabolomicsS10OD012304 · OD · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI HAWKE, DAVID H · 2013 to 2013
$877kNCI NIH HHS P30 CA016672NCI NIH HHS P50 CA100632NCI NIH HHS R01 CA231364NCI NIH HHS R35 CA210065NIGMS NIH HHS R01 GM134382NIH HHS S10 OD012304
Abstract
T-cell acute lymphoblastic leukemia (T-ALL) is commonly driven by activating mutations in NOTCH1 that facilitate glutamine oxidation. Here we identify oxidative phosphorylation (OxPhos) as a critical pathway for leukemia cell survival and demonstrate a direct relationship between NOTCH1, elevated OxPhos gene expression, and acquired chemoresistance in pre-leukemic and leukemic models. Disrupting OxPhos with IACS-010759, an inhibitor of mitochondrial complex I, causes potent growth inhibition through induction of metabolic shut-down and redox imbalance in NOTCH1-mutated and less so in NOTCH1-wt T-ALL cells. Mechanistically, inhibition of OxPhos induces a metabolic reprogramming into glutaminolysis. We show that pharmacological blockade of OxPhos combined with inducible knock-down of glutaminase, the key glutamine enzyme, confers synthetic lethality in mice harboring NOTCH1-mutated T-ALL. We leverage on this synthetic lethal interaction to demonstrate that IACS-010759 in combination with chemotherapy containing L-asparaginase, an enzyme that uncovers the glutamine dependency of leukemic cells, causes reduced glutaminolysis and profound tumor reduction in pre-clinical models of human T-ALL. In summary, this metabolic dependency of T-ALL on OxPhos provides a rational therapeutic target.
Indexed as
Precursor T-Cell Lymphoblastic Leukemia-LymphomaAnimalsElectron Transport Complex IGlutamineMiceReceptor, Notch1T-LymphocytesElectron Transport Complex IGlutamineReceptor, Notch1
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