The BCL6 gene, isolated from the breakpoints of 3q27-associated chromosomal translocations, has been implicated in diffuse large B-cell lymphomas (DLBL). Here we describe the molecular characterization of novel t(3;7)(q27;p12) translocations in 2 patients with DLBL. Molecular genetic analysis of the breakpoint area involving BCL6 revealed the presence of the Ikaros gene, a central regulator of lymphoid differentiation that had been mapped to human chromosome 7 band p13-p11.1. As a molecular consequence of the translocation, the 5' regulatory region of the BCL6 gene was replaced by the putative 5' regulatory region of the Ikaros gene, probably leading to deregulated expression of the BCL6 gene throughout B-cell differentiation. Reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH) analyses of a patient sample established that the t(3;7)(q27;p12) results in fusion of the Ikaros and BCL6 genes. This study provides the first evidence that the Ikaros gene is rearranged in human hematopoietic malignant disorders. (Blood. 2000;95:2719-2721)