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

Abstract

SummaryThe 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.