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Background: Accumulation of genetic aberrations in MDS is closely associated with progression to AML. FLT3-ITD is commonly found in AML and less frequently in MDS. FLT3-ITD in MDS is associated with a high risk of transformation to AML. Recently, significant interaction of NPM1^(mt) and FLT3-ITD was described in AML. This study was conducted to investigate the incidence and prognostic role of FLT3-ITD and NPM1 mutations NPM1^(mt) on paired samples at diagnosis of MDS and AML. Methods: Patients who were diagnosed as MDS transforming to AML were included. FLT3-ITD was detected by PCR, and NPM1^(mt) was confirmed by direct sequencing after screening for NPM by immunohistochemistry. Results: AML developed in 12.0% (43/357) of MDS patients. FLT3-ITD was detected in none of MDS and 14.7% (5/34) of AML. NPM1mt was detected in 2.4% (1/41) of MDS and 11.6% (5/43) of AML. One patient with type B NPM1mt at MDS transformed to type A NPM1^(mt) at AML. FLT3-ITD positive AML showed a tendency of shorter survival and a significantly longer time to achieve complete remission than FLT3-ITD negative AML(P =0.007). Normal karyotype AML with FLT3-ITD showed shorter overall survival than that group of AML without FLT3-ITD (P =0.017). Conclusions: MDS patients acquired FLT3-ITD during AML transformation, and FLT3-ITD positive AML, especially that with normal karyotype,predicted a poor outcome. NPM1^(mt) was identified in both MDS and AML. NPM1mt was rarely found in MDS patients, and mostly was acquired after AML transformation. Clonal evolution of NPM1^(mt) subtype was found in one patient during acute transformation.