We recently isolated the RhoH/TTF gene by its fusion to the LAZ3/BCL6 gene, in a non-Hodgkin's lymphoma (NHL) cell line, which bore at (3; 4)(q27; p11–13) translocation. This gene encodes a novel Rho GTP-binding protein and is specifically expressed in hematopoietic tissues. We made its precise mapping at band 4p13, and described its partial genomic structure. Using fluorescence in situ hybridization and molecular analyses, we report here on the rearrangement of the RhoH/TTF gene, at band 4p13, in four cases of NHL with t (3; 4)(q27; p13) translocation and its fusion to the LAZ3/BCL6 gene at band 3q27, in three of these cases. RT–PCR analysis of two cases allowed the detection of variable fusion transcripts emerging from the rearranged alleles, and in one case, a deregulated expression of both RhoH/TTF and LAZ3/BCL6 genes, by promoter substitution, was observed. We also show here another rearrangement of the RhoH/TTF gene in a patient with multiple myeloma and t (4; 14)(p13; q32) translocation, with breakage within the IGH gene. It is the first report which describes the recurrent chromosomal alteration of a GTP-binding protein encoding gene, in patients with hematopoietic malignancies.