PVRL2 Is Translocated to the TCRA Locus in t(14;19)(q11;13) Positive Peripheral T-Cell Lymphoma.

T-cell non-Hodgkin lymphomas (NHLs) are uncommon malignancies that represent approximately 15% of aggressive lymphomas in Western countries. Contrasting with B-cell lymphomas, very few recurrent chromosomal abnormalities have been identified. Nevertheless, the TCR loci and preferentially the TCRAD at chromosome band 14q11 could be involved in up to 15% of cases. We recently reported a novel and recurrent t(14;19)(q11;q13) chromosomal translocation in peripheral T-cell lymphoma (PTCL). FISH analysis performed in three cases suggested an implication of the TCRAD locus at 14q11 and of BCL3 at 19q13. We now report the molecular cloning of the genomic junctions for these three patients. Sequence analysis confirmed the involvement of the TCRAD on 14q11 and assessed the breakpoint’s localisation to the TCRA variable region for all cases. In the first, the chromosomal break occurred between the J30 and the J31 segments while in the second it was in the J58 segment. Thus, both translocations probably occurred after an illegitimate V(D)J recombination. Remarkably, for the third patient, junctions with the deltaRec and psi(J)alpha elements were identified on the der(14) and der(19) respectively. Consequently this translocation probably results from an illegitimate deltarec-Psi(J)alpha rearrangement (TCRD deletion) during thymopoiesis before Valpha-Jalpha rearrangements. On chromosome 19, our results indicated a new clustering of breakpoints outside the region documented in t(14;19)(q32;q13) in chronic lymphocytic leukemia. Remarkably, all three breaks occurred ~130kb downstream from BCL3, in the PVRL2 gene. Consequently, the TCRA locus enhancer is juxtaposed to PVRL2 and BCL3 on the derivative chromosome 19. For two patients, mRNA expression levels were investigated by real time RT-PCR experiments, which confirmed a high expression of both PVRL2 and BCL3. In conclusion, we identified PVRL2 as the recurrent translocation partner of the TCRA locus in PTCL. Whether this clustering results from an important instability of the PVRL2 gene during thymopoiesis remains to be investigated. The PVRL2 overexpression itself may be an important step for T-cell lymphomagenesis.