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Acute myeloid leukemia (AML) with normal cytogenetics represents approximately 40% to 50% of de novo AML. This heterogeneous AML subgroup constitutes the single largest cytogenetic group with an intermediate prognosis. Previous studies have suggested that the Fms-like tyrosine kinase-3 internal tandem duplication (FLT3/ITD) mutation–positive de novo AML may represent a distinctive subgroup of AML. We analyzed the clinical and pathologic features of 15 cases of de novo AML with normal cytogenetics and with the FLT3/ITD mutation. In comparison with patients with AML without the FLT3/ITD mutation, patients with FLT3/ITD+ AML are relatively younger, more often have marked peripheral leukocytosis with a higher number of circulating blasts at initial examination, more often have minimal differentiation morphologic features, more frequently have abnormal CD7 coexpression, and have poorer outcome. Close association of aberrant CD7 expression and FLT3/ ITD mutation in the myeloblasts of FLT3/ITD+ AML suggests that FLT3/ITD-mediated leukemic transformation occurs in the more early stage of myeloid progenitor cells.