Prognostic impact of FLT3-ITD mutation on NPM1+ acute myeloid leukaemia patients and related molecular mechanisms

Abstract

The prognosis of acute myeloid leukaemia (AML) patients carrying NPM1 mutations is significantly worse when accompanied by FLT3-ITD mutations. However, accurate quantitative detection of FLT3-ITD mutations remains challenging. To identify a novel biomarker in NPM1⁺ FLT3-ITD⁺ AML patients for more accurate stratification, we analysed the differential gene expression between the NPM1⁺ FLT3-ITD⁺ and NPM1⁺ FLT3-ITD^- groups in five public AML datasets and identified a biomarker by taking the intersection of differentially expressed genes. We validated this biomarker in bone marrow samples from NPM1⁺ AML patients at the Peking University Institute of Haematology and analysed its prognostic significance. BCAT1 expression was higher in the NPM1⁺ FLT3-ITD⁺ group than in the NPM1⁺ FLT3-ITD^- group in all seven cohorts. BCAT1 was able to predict the prognosis of NPM1⁺ FLT3-ITD⁺ AML patients, and its predictive ability was superior to that of the FLT3-ITD allelic ratio (AR). FLT3-targeted inhibitor quizartinib reduced BCAT1 expression. BCAT1 knockdown using lentiviral vectors led to the downregulation of MYC expression. Thus, we identified BCAT1 as a novel biomarker for NPM1⁺ FLT3-ITD⁺ AML patients. The FLT3-ITD/BCAT1/MYC signalling pathway may play a biological role in promoting the occurrence and development of AML in FLT3-ITD⁺ cell lines.

Keywords: BCAT1; FLT3-ITD mutation; NPM1 mutation; acute myeloid leukaemia.