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To determine the incidence of MLLrearrangement in acute myeloid leukemia (AMU French-American-British (FAB) type M1 and to evaluate optimal screening strategies for the characterization of such abnormalities, we analyzed specimens from 41 patients with AML by Southern blotting with two MLLgenomic probes and compared the capacities of reverse transcription-polymerase chain reaction (RT-PCR) and fluorescent in situ hybridization (FISH) to identify the types of rearrangement found in AML M1 with those observed in AML M5. MLLrearrangement was found in 6 of 29 (20%) AML M1 and 6 of 10 AML M5 cases. RT-PCR characterization of 11 cases showed four MLLself-fusions, four MLL-AF6, two MLL-AF9, including a novel AF9breakpoint, and one uncharacterized t(11;19). Only 5 of 10 MLL-rearranged cases tested demonstrated karyotypic 11q23 abnormalities. FISH analysis of nine cases with an MLL-specific yeast artificial chromosome (YAC) confirmed the cytogenetic abnormalities in two cases, clarified them in one, and did not detect six cases, including three MLLself-fusions, one case with a probable Mil-rearranged subclone not represented karyo-typically, and two MLL-AF6.A whole chromosome 11 paint detected one of these MLL-AF6, and an AF6cosmid demonstrated that the other was probably due to insertion of a submicroscopic portion of chromosome 6, including part of AF6, into an apparently normal chromosome 11. We conclude that MLLrearrangements are common in adult AML M1, that MLLself-fusion and MLL-AF6are the most frequent types of abnormalities, and that RT-PCR is preferable to 11q23 FISH analysis for their characterization.