Glutaminolysis is a metabolic dependency in FLT3 acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.

TitleGlutaminolysis is a metabolic dependency in FLT3 acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition.
Publication TypeJournal Article
Year of Publication2018
AuthorsGallipoli, P, Giotopoulos, G, Tzelepis, K, Costa, ASH, Vohra, S, Medina-Perez, P, Basheer, F, Marando, L, Di Lisio, L, Dias, JML, Yun, H, Sasca, D, Horton, SJ, Vassiliou, G, Frezza, C, Huntly, BJP
JournalBlood
Volume131
Issue15
Pagination1639-1653
Date Published2018 04 12
ISSN1528-0020
KeywordsCRISPR-Cas Systems, Enzyme Activation, fms-Like Tyrosine Kinase 3, Genome-Wide Association Study, Glutamine, Humans, K562 Cells, Leukemia, Myeloid, Acute, Mutation, Protein Kinase Inhibitors, THP-1 Cells
Abstract

FLT3 internal tandem duplication (FLT3) mutations are common in acute myeloid leukemia (AML) associated with poor patient prognosis. Although new-generation FLT3 tyrosine kinase inhibitors (TKI) have shown promising results, the outcome of FLT3 AML patients remains poor and demands the identification of novel, specific, and validated therapeutic targets for this highly aggressive AML subtype. Utilizing an unbiased genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 screen, we identify GLS, the first enzyme in glutamine metabolism, as synthetically lethal with FLT3-TKI treatment. Using complementary metabolomic and gene-expression analysis, we demonstrate that glutamine metabolism, through its ability to support both mitochondrial function and cellular redox metabolism, becomes a metabolic dependency of FLT3 AML, specifically unmasked by FLT3-TKI treatment. We extend these findings to AML subtypes driven by other tyrosine kinase (TK) activating mutations and validate the role of GLS as a clinically actionable therapeutic target in both primary AML and in vivo models. Our work highlights the role of metabolic adaptations as a resistance mechanism to several TKI and suggests glutaminolysis as a therapeutically targetable vulnerability when combined with specific TKI in FLT3 and other TK activating mutation-driven leukemias.

DOI10.1182/blood-2017-12-820035
Alternate JournalBlood
Citation Key10.1182/blood-2017-12-820035
PubMed ID29463564
PubMed Central IDPMC6061932
Grant ListMC_UU_12022/6 / / Medical Research Council / United Kingdom
14-1069 / / Worldwide Cancer Research / United Kingdom
MR/M010392/1 / / Medical Research Council / United Kingdom
/ / Wellcome Trust / United Kingdom
MC_PC_12009 / / Medical Research Council / United Kingdom
G1000288 / / Medical Research Council / United Kingdom
109967/Z/15/Z / / Wellcome Trust / United Kingdom
C56179/A21617 / / Cancer Research UK / United Kingdom