Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition

Paolo Gallipoli, George Giotopoulos, Konstantinos Tzelepis, Ana S.H. Costa, Shabana Vohra, Paula Medina-Perez, Faisal Basheer, Ludovica Marando, Lorena Di Lisio, Joao M.L. Dias, Haiyang Yun, Daniel Sasca, Sarah J. Horton, George Vassiliou, Christian Frezza and Brian J.P. Huntly

Key points

  • FLT3ITD tyrosine kinase (TK) inhibition impairs glycolysis and glucose utilization without equally affecting glutamine metabolism

  • Combined targeting of FLT3 TK activity and glutamine metabolism decreases FLT3ITD mutant cells leukemogenic potential in vitro and in vivo


FLT3 internal tandem duplication (FLT3ITD) are common mutations 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 FLT3ITD 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 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 FLT3ITD 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 FLT3ITD and other TK activating mutation driven leukemias.

  • Submitted December 4, 2017.
  • Accepted February 14, 2018.