The Philadelphia (Ph) translocation t(9;22)(q34;q11) occurs frequently in chronic myeloid leukemia (CML) but is less common in acute lymphoblastic leukemia (ALL) and rare in acute myeloid leukemia (AML). In most cases of CML and some cases of Ph+ ALL the protooncogene ABL from 9q34 is translocated to the breakpoint cluster region (bcr) of the BCR gene at 22q11 to form a chimeric gene encoding a novel 210-kd protein (P210 BCR-ABL) with enhanced tyrosine kinase activity. In other patients with Ph+ ALL and Ph+ AML, the breakpoint probably occurs in the first intron of the BCR gene; this results in a smaller chimeric gene which encodes a P190 BCR-ABL. We studied a patient with AML (FAB M6) arising de novo who had a "masked" Ph chromosome in association with extensive karyotypic changes. The leukemic cells initially showed rearrangement of the bcr, presence of a hybrid mRNA, and expression of the P210 BCR-ABL. These changes were absent in remission. These results support the concept that the BCR-ABL chimeric gene plays a crucial role in leukemogenesis but suggest that factors other than the position of the breakpoint in the BCR gene determine the lineage of the target cell for malignant transformation.