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The LAZ3(BCL6) gene on chromosome band 3q27 is nonrandomly disrupted in B-cell non-Hodgkin lymphoma (B-NHL) by chromosomal translocations clustered within a 3.3-kb MTC (major translocation cluster) located between the two first noncoding exons. These translocations generally result in the expression of a chimeric mRNA transcript between the LAZ3 gene and sequences derived from the partner chromosome. Using RACE RT-PCR, we previously demonstrated fusion of LAZ3 with the RhoH/TTF gene, a hemopoietic cell-specific small GTPase involved in cytoskeleton organization, and with the BOB1/OBF1 gene, a B-cell-specific coactivator of octamer-binding transcription factors, following translocations t(3;4)(q27;p13) and t(3;11)(q27;q23), respectively. Here we report the identification of the L-Plastin(LCP1) gene as a novel LAZ3 partner in chimeric transcripts resulting from a t(3;13)(q27;q14) translocation, in two cases of B-cell lymphoma. As a consequence of the translocation, the 5' regulatory region of each gene was exchanged, creating both LCP1-LAZ3 and reciprocal LAZ3-LCP1 fusion transcripts in one case, and only a LCP1-LAZ3 fusion transcript in the other. The 13q14 chromosome region is frequently disrupted in various proliferative disorders, and the LCP1 gene defines a new breakpoint site in this region. This gene encodes an actin-binding protein and is the second LAZ3 partner gene, with the RhoH/TTF gene, involved in actin cytoskeleton organization. Genes Chromosomes Cancer 26:97-105, 1999.

The LAZ3/BCL6 gene on chromosone 3q27 is recurrently disrupted in B cell non-Hodgkin's lymphomas by translocations involving immunoglobulin genes or other chromosone regions. We have cloned the breakpoint region and chromosone derivatives of the t(3;11)(q27;q23.1) translocation, present in a B cell leukemia cell line (Karpas 231), which define a novel 11q23.1 breakpoint site. As a consequence of the translocation, LAZ3 regulatory regions upstream of non-coding exon 2 are replaced by those of BOB1/OBF1, a recently described B cell-specific coactivator of octamer-binding transcription factors. A detailed structural study of the BOB1/OBF1 genomic DNA and of a nearly full-length cDNA revealed particular features in the 3' untranslated region, such as an Alu motif and a polymorphic tetranucleotide microsatellite. Two mutations leading to two potential amino acid changes in the C-terminal region, were also detected in one allele of a lymphoma B cell line, Raji. Due to its cell-specific expression and role as a coactivating transcription factor, chromosomal translocation and/or point mutation of BOB1/OBF1 may contribute to B cell tumorigenesis.

The LAZ3/BCL6 gene on chromosome 3q27 is recurrently disrupted in B-cell non Hodgkin's lymphomas by translocations involving immunoglobulin genes or other chromosome regions. We have studied the t(3; 11) (q27; q23) translocation, present in a B-cell leukemia cell line (Karpas 231). As a consequence of this translocation, a LAZ3 chimeric transcript was created by fusion, 5' to the LAZ3 exon 2, with a transcribed sequence identical to BOB1/OBF1, a B cell-specific coactivator of octamer-binding transcription factors, recently described. Nucleotidic sequence of a nearly full-length cDNA of the BOB1/OBF1 gene revealed particular features in the 3' untranslated region of the gene, including pyrimidine-rich sequence repeats, an Alu motif, and a polymorphic [CCTT] tetranucleotide microsatellite. Two A to G transition mutations were also detected in the coding region of one allele of a lymphoma B-cell line, Raji, leading to 2 amino-acid changes in the C-terminal region. Due to its cell-specificity and role as a coactivating transcription factor, chromosomal translocation and/or perhaps point mutation of BOB1/OBF1 may contribute to B cell tumorigenesis.

We have previously shown that the LAZ3/BCL6 gene encoding a potential transcription factor, is disrupted in B-diffuse large cell non-Hodgkin's lymphomas (NHL) with 3q27 chromosomal abnormalities involving the immunoglobulin (IG) genes. However, LAZ3 rearrangement also occurs in NHL bearing 3q27 translocations without involvement of the IG genes: for example the VAl cell line exhibits t(3;4)(q27;p11). In the present work we have used a RT-PCR method to detect and to sequence the LAZ3 mRNA products from the VAL cell line. We report that the consequence of the t(3;4) is the expression of a chimeric transcript of LAZ3 with a new gene encoding a small G-like protein, termed TTF (Translocation Three Four). Nucleotide sequence analysis of a 1.4 kb cDNA predicts that the TTF gene encodes a protein of 191 amino-acids similar to members of the RAS superfamily including HRAS (27% identical), RAB1A (30% identical) and RHO proteins: the human RAC1, RHOB and CDC42Hs proteins (respectively 43, 44 and 45% identical) and the yeast RHO2 protein (44% identical). Unlike most other small G proteins which are expressed ubiquitously, TTF was transcribed only in hemopoietic cells as a 2.2 kb transcript. TTF may define a new subgroup of RHO-like proteins.

In B-cell malignancies, the t(11;14)(q13;q32) at the 11q13 BCL1 locus is characterized by a scattering of breakpoint sites along a 100 kb genomic region, between the BCL1 major translocation cluster (MTC) and the PRAD1 (also termed cyclin D1 or CCND1) gene. Recently, the 11q13 breakpoint region was extended on both sides, centromeric to the MTC and telomeric to PRAD1. We report here the molecular cloning of a new t(11;14) breakpoint site, 20 kb centromeric to the MTC, from a patient with prolymphocytic leukemia. We subcloned a non-repetitive DNA fragment near the breakpoint and mapped this new 11q13 probe (pHO11c) relative to already identified breakpoint sites, using long- and short-range physical mapping within the BCL1 locus. Rearrangements in the BCL1 locus are associated with deregulation of the PRAD1 gene, which is often overexpressed, particularly in mantle-cell malignancies. The detectable but weak PRAD1 expression in the case we present suggests that this breakpoint centromeric to the MTC still lies inside the BCL1 locus boundaries. We think that attention should be focused on this region centromeric to the BCL1-MTC, where the investigation of previously unidentified translocations may increase understanding of the PRAD1 gene deregulation in t(11;14) associated pathologies.