INTERNAL TANDEM DUPLICATION OF FLT3 ASSOCIATED WITH LEUKOCYTOSIS IN ACUTE PROMYELOCYTIC LEUKEMIA

FLT3 is a member of receptor tyrosine kinases expressed in leukemia ce lls, as well as in hematopoietic stem cells. Recently, a somatic alter ation of the FLT3 gene was found in acute myeloid leukemia, as an inte rnal tandem duplication (FLT3/ITD) which caused elongation of the juxt amembrane (JM) domain of FLT3. Here we characterized the FLT3/ITD and investigated its clinical significance in acute promyelocytic leukemia (APL). Seventy-four newly diagnosed patients with APL, who were treat ed with the same protocol in a multi-institutional study, were studied for the FLT3/ITD. Genomic and message sequences of the FLT3 gene were amplified by means of polymerase chain reaction (PCR), and elongated PCR products were sequenced. Fifteen patients (20.3%) had FLT3/ITD, al l of which were transcribed in frame. Location of the duplicated fragm ents (six to 30 amino acids) varied from patient to patient. However, they always contained either Y591 or Y599, but the tyrosine kinase dom ain was not significantly affected. This finding implied that signal t ransduction of FLT3 is amplified by the duplication. Clinically, the p resence of FLT3/ITD was related to high peripheral white blood cell co unts as well as peripheral leukemia cell counts (P < 0.0001), high LDH level (P = 0.04), and low fibrinogen concentration (P = 0.04). These data suggest that FLT3/ITD plays a significant role in progression of APL.