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

ABSTRACT: FLT3 internal tandem duplication (FLT3^ITD) 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^ITD 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

SUBMITTER: Gallipoli P 

PROVIDER: S-EPMC6061932 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature