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In acute myeloid leukemia (AML), activating mutations in the FLT3 gene occur in 30% to 40% of adult patients and play a crucial role in proliferation and survival of the leukemic clone. Twenty percent to 30% of AML patients harbour an internal tandem duplication (ITD) within FLT3. Generally, it is believed that the ITD insertions within FLT3 occur in the JM domain. However, recently, we reported the identification of FLT3_ITD mutations located in non-JM domains of the FLT3-receptor. This novel type of FLT3_ITD receptors was found in 28.7% of cases from a large cohort of unselected FLT3_ITD-positive AML patients (n=753). On a clinical level, ITD integration in the beta1-sheet of FLT3 was identified as a negative predictor for achievement of complete remission and for duration of relapse-free and overall survival (Kayser-S et al., Blood 2009). In addition, we showed that FLT3 internal tandem duplications (ITD) displaying insertion sites within TKD-1 mediate differential responsiveness to FLT3-TKIs in vitro. Thus, our results indicate that a significant proportion of activating FLT3_ITD mutations is not confined to the JM domain of FLT3. The data suggest that particular ITDs of FLT3 may be associated with differential biological and clinical.