PMID- 35589701
OWN - NLM
STAT- MEDLINE
DCOM- 20220523
LR  - 20230421
IS  - 2041-1723 (Electronic)
IS  - 2041-1723 (Linking)
VI  - 13
IP  - 1
DP  - 2022 May 19
TI  - Inhibition of mitochondrial complex I reverses NOTCH1-driven metabolic 
      reprogramming in T-cell acute lymphoblastic leukemia.
PG  - 2801
LID - 10.1038/s41467-022-30396-3 [doi]
LID - 2801
AB  - 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.
CI  - (c) 2022. The Author(s).
FAU - Baran, Natalia
AU  - Baran N
AUID- ORCID: 0000-0003-0618-4798
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Lodi, Alessia
AU  - Lodi A
AD  - Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell 
      Medical School, The University of Texas at Austin, Austin, TX, USA.
FAU - Dhungana, Yogesh
AU  - Dhungana Y
AD  - St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research 
      Hospital, Memphis, TN, USA.
FAU - Herbrich, Shelley
AU  - Herbrich S
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Collins, Meghan
AU  - Collins M
AUID- ORCID: 0000-0002-6201-9298
AD  - Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell 
      Medical School, The University of Texas at Austin, Austin, TX, USA.
FAU - Sweeney, Shannon
AU  - Sweeney S
AD  - Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell 
      Medical School, The University of Texas at Austin, Austin, TX, USA.
FAU - Pandey, Renu
AU  - Pandey R
AD  - Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell 
      Medical School, The University of Texas at Austin, Austin, TX, USA.
FAU - Skwarska, Anna
AU  - Skwarska A
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Patel, Shraddha
AU  - Patel S
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Tremblay, Mathieu
AU  - Tremblay M
AD  - Institute for Research in Immunology and Cancer, The University of Montreal, 
      Montreal, QC, Canada.
FAU - Kuruvilla, Vinitha Mary
AU  - Kuruvilla VM
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Cavazos, Antonio
AU  - Cavazos A
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Kaplan, Mecit
AU  - Kaplan M
AUID- ORCID: 0000-0003-0079-8617
AD  - Department of Stem Cell Transplantation and Cellular Therapy, The University of 
      Texas MD Anderson Cancer Center, Houston, TX, USA.
FAU - Warmoes, Marc O
AU  - Warmoes MO
AD  - Department of Bioinformatics and Computational Biology, The University of Texas 
      MD Anderson Cancer Center, Houston, TX, USA.
FAU - Veiga, Diogo Troggian
AU  - Veiga DT
AD  - The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
FAU - Furudate, Ken
AU  - Furudate K
AUID- ORCID: 0000-0003-1272-5490
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
AD  - Department of Oral and Maxillofacial Surgery, Hirosaki University Graduate School 
      of Medicine, Hirosaki, Aomori, Japan.
FAU - Rojas-Sutterin, Shanti
AU  - Rojas-Sutterin S
AD  - Institute for Research in Immunology and Cancer, The University of Montreal, 
      Montreal, QC, Canada.
FAU - Haman, Andre
AU  - Haman A
AD  - Institute for Research in Immunology and Cancer, The University of Montreal, 
      Montreal, QC, Canada.
FAU - Gareau, Yves
AU  - Gareau Y
AD  - Institute for Research in Immunology and Cancer, The University of Montreal, 
      Montreal, QC, Canada.
FAU - Marinier, Anne
AU  - Marinier A
AUID- ORCID: 0000-0002-0116-8345
AD  - Institute for Research in Immunology and Cancer, The University of Montreal, 
      Montreal, QC, Canada.
FAU - Ma, Helen
AU  - Ma H
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Harutyunyan, Karine
AU  - Harutyunyan K
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Daher, May
AU  - Daher M
AD  - Department of Stem Cell Transplantation and Cellular Therapy, The University of 
      Texas MD Anderson Cancer Center, Houston, TX, USA.
FAU - Garcia, Luciana Melo
AU  - Garcia LM
AD  - Department of Stem Cell Transplantation and Cellular Therapy, The University of 
      Texas MD Anderson Cancer Center, Houston, TX, USA.
FAU - Al-Atrash, Gheath
AU  - Al-Atrash G
AD  - Department of Stem Cell Transplantation and Cellular Therapy, The University of 
      Texas MD Anderson Cancer Center, Houston, TX, USA.
FAU - Piya, Sujan
AU  - Piya S
AUID- ORCID: 0000-0002-8976-540X
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Ruvolo, Vivian
AU  - Ruvolo V
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Yang, Wentao
AU  - Yang W
AD  - Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 
      Memphis, TN, USA.
FAU - Shanmugavelandy, Sriram Saravanan
AU  - Shanmugavelandy SS
AD  - Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer 
      Center, Houston, TX, USA.
FAU - Feng, Ningping
AU  - Feng N
AD  - TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. 
      Anderson Cancer Center, Houston, USA.
FAU - Gay, Jason
AU  - Gay J
AD  - TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. 
      Anderson Cancer Center, Houston, USA.
FAU - Du, Di
AU  - Du D
AUID- ORCID: 0000-0002-8851-8466
AD  - Department of Bioinformatics and Computational Biology, The University of Texas 
      MD Anderson Cancer Center, Houston, TX, USA.
FAU - Yang, Jun J
AU  - Yang JJ
AUID- ORCID: 0000-0002-0770-9659
AD  - Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, 
      Memphis, TN, USA.
FAU - Hoff, Fieke W
AU  - Hoff FW
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Kaminski, Marcin
AU  - Kaminski M
AUID- ORCID: 0000-0002-9026-0185
AD  - Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, 
      USA.
FAU - Tomczak, Katarzyna
AU  - Tomczak K
AD  - Department of Translational Molecular Pathology, The University of Texas MD 
      Anderson Cancer Center, Houston, TX, USA.
FAU - Eric Davis, R
AU  - Eric Davis R
AUID- ORCID: 0000-0001-7311-0065
AD  - Department of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer 
      Center, Houston, TX, USA.
FAU - Herranz, Daniel
AU  - Herranz D
AUID- ORCID: 0000-0003-1768-5969
AD  - Rutgers Robert Wood Johnson Medical School, Cancer Institute of New Jersey, New 
      Brunswick, NJ, USA.
FAU - Ferrando, Adolfo
AU  - Ferrando A
AUID- ORCID: 0000-0002-6212-8574
AD  - Irving Cancer Research Center, Columbia University Irving Medical Center, New 
      York, NY, USA.
FAU - Jabbour, Elias J
AU  - Jabbour EJ
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Emilia Di Francesco, M
AU  - Emilia Di Francesco M
AD  - Institute for Applied Cancer Science, The University of Texas MD Anderson Cancer 
      Center, Houston, TX, USA.
FAU - Teachey, David T
AU  - Teachey DT
AUID- ORCID: 0000-0001-7373-8987
AD  - Perelman School of Medicine, The University of Pennsylvania, Philadelphia, PA, 
      USA.
FAU - Horton, Terzah M
AU  - Horton TM
AUID- ORCID: 0000-0001-8293-4242
AD  - Texas Children's Cancer Center, Baylor College of Medicine, Houston, TX, USA.
FAU - Kornblau, Steven
AU  - Kornblau S
AUID- ORCID: 0000-0002-5990-9548
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Rezvani, Katayoun
AU  - Rezvani K
AD  - Department of Stem Cell Transplantation and Cellular Therapy, The University of 
      Texas MD Anderson Cancer Center, Houston, TX, USA.
FAU - Sauvageau, Guy
AU  - Sauvageau G
AD  - Institute for Research in Immunology and Cancer, The University of Montreal, 
      Montreal, QC, Canada.
FAU - Gagea, Mihai
AU  - Gagea M
AUID- ORCID: 0000-0002-2399-1375
AD  - Department of Veterinary Medicine and Surgery, The University of Texas MD 
      Anderson Cancer Center, Houston, TX, USA.
FAU - Andreeff, Michael
AU  - Andreeff M
AUID- ORCID: 0000-0002-1144-1958
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Takahashi, Koichi
AU  - Takahashi K
AUID- ORCID: 0000-0002-8027-9659
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA.
FAU - Marszalek, Joseph R
AU  - Marszalek JR
AD  - TRACTION Platform, Therapeutics Discovery Division, University of Texas M. D. 
      Anderson Cancer Center, Houston, USA.
FAU - Lorenzi, Philip L
AU  - Lorenzi PL
AUID- ORCID: 0000-0003-0385-7774
AD  - Department of Bioinformatics and Computational Biology, The University of Texas 
      MD Anderson Cancer Center, Houston, TX, USA.
FAU - Yu, Jiyang
AU  - Yu J
AUID- ORCID: 0000-0003-3629-4330
AD  - Department of Computational Biology, St. Jude Children's Research Hospital, 
      Memphis, TN, USA.
FAU - Tiziani, Stefano
AU  - Tiziani S
AD  - Department of Nutritional Sciences, Dell Pediatric Research Institute, Dell 
      Medical School, The University of Texas at Austin, Austin, TX, USA.
FAU - Hoang, Trang
AU  - Hoang T
AD  - Institute for Research in Immunology and Cancer, The University of Montreal, 
      Montreal, QC, Canada.
AD  - Department of Pharmacology and Physiology, Faculty of Medicine, University of 
      Montreal, Montreal, QC, Canada.
FAU - Konopleva, Marina
AU  - Konopleva M
AUID- ORCID: 0000-0002-9347-2212
AD  - Department of Leukemia, The University of Texas MD Anderson Cancer Center, 
      Houston, TX, USA. mkonople@mdanderson.org.
LA  - eng
GR  - R35 CA210065/CA/NCI NIH HHS/United States
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - R01 CA231364/CA/NCI NIH HHS/United States
GR  - P50 CA100632/CA/NCI NIH HHS/United States
GR  - S10 OD012304/OD/NIH HHS/United States
GR  - R01 GM134382/GM/NIGMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220519
PL  - England
TA  - Nat Commun
JT  - Nature communications
JID - 101528555
RN  - 0 (Receptor, Notch1)
RN  - 0RH81L854J (Glutamine)
RN  - EC 7.1.1.2 (Electron Transport Complex I)
SB  - IM
MH  - Animals
MH  - Electron Transport Complex I/genetics/metabolism
MH  - Glutamine/metabolism
MH  - Mice
MH  - *Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug 
      therapy/genetics/metabolism
MH  - Receptor, Notch1/metabolism
MH  - T-Lymphocytes/metabolism
PMC - PMC9120040
COIS- The authors declare no competing interests.
EDAT- 2022/05/20 06:00
MHDA- 2022/05/24 06:00
PMCR- 2022/05/19
CRDT- 2022/05/19 23:14
PHST- 2021/04/06 00:00 [received]
PHST- 2022/04/25 00:00 [accepted]
PHST- 2022/05/19 23:14 [entrez]
PHST- 2022/05/20 06:00 [pubmed]
PHST- 2022/05/24 06:00 [medline]
PHST- 2022/05/19 00:00 [pmc-release]
AID - 10.1038/s41467-022-30396-3 [pii]
AID - 30396 [pii]
AID - 10.1038/s41467-022-30396-3 [doi]
PST - epublish
SO  - Nat Commun. 2022 May 19;13(1):2801. doi: 10.1038/s41467-022-30396-3.