期刊
BLOOD
卷 131, 期 15, 页码 1639-1653出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-12-820035
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资金
- Wellcome Trust [109967/Z/15/Z]
- Academy of Medical Sciences
- Lady Tata Memorial Trust
- European Research Council
- Medical Research Council
- Bloodwise
- Kay Kendall Leukaemia Fund
- Cambridge National Institute for Health Research Biomedical Research Centre
- Cancer Research UK [C56179/A21617]
- Cambridge Institute for Medical Research Flow Cytometry Core Facility
- Wellcome Trust [109967/Z/15/Z] Funding Source: Wellcome Trust
- Academy of Medical Sciences (AMS) [AMS-SGCL10-Gallipoli] Funding Source: researchfish
- Cancer Research UK [23015, 25508] Funding Source: researchfish
- European Hematology Association [TRTH157] Funding Source: researchfish
- Medical Research Council [MC_PC_12009, MR/M010392/1, MR/R009708/1, MC_UU_12022/6, G1000288] Funding Source: researchfish
- Wellcome Trust [109967/Z/15/Z] Funding Source: researchfish
- Worldwide Cancer Research [14-1069] Funding Source: researchfish
- MRC [MR/R009708/1, MC_UU_12022/6, G1000288, MR/M010392/1] Funding Source: UKRI
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 genomewide 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(ITD) AML, specifically unmasked by FLT3-TKI treatment. We extend thesefindings 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(ITD) and other TK activating mutation-driven leukemias.
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