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

Gallipoli 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 (2018)

Publication Type: Journal article

Publication year: 2018

Journal

Blood American Society of Hematology

Book Volume: 131

Pages Range: 1639-1653

Journal Issue: 15

DOI: 10.1182/blood-2017-12-820035

Abstract

FLT3 internal tandem duplication (FLT3ITD) 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 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 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 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.

Additional Organisation(s)

Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

University of Cambridge GB United Kingdom (GB) Wellcome Trust Sanger Institute - Genome Research Limited GB United Kingdom (GB)

How to cite

APA:

Gallipoli, P., Giotopoulos, G., Tzelepis, K., Costa, A.S.H., Vohra, S., Medina-Perez, P.,... Huntly, B.J.P. (2018). Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition. Blood, 131(15), 1639-1653. https://dx.doi.org/10.1182/blood-2017-12-820035

MLA:

Gallipoli, Paolo, et al. "Glutaminolysis is a metabolic dependency in FLT3ITD acute myeloid leukemia unmasked by FLT3 tyrosine kinase inhibition." Blood 131.15 (2018): 1639-1653.

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