FOXP1, a Highly Expressed Gene in a Subset of DLBCL, Is Targeted by a Recurrent t(3;14)(p13;q32).

Chromosomal translocations involving the immunoglobulin heavy chain genes cluster (IGH) at 14q32 have been found in up to 70% of B-non Hodgkin’s lymphoma. These aberrations lead to deregulation of putative oncogenes by their juxtaposition with IGH enhancer elements. So far, more than 20 genes affected by t(14q32) have been identified in B-cell malignancies. The most frequently rearranged genes include BCL1/11q13, BCL2/18q21, BCL6/3q27 and CMYC/8q24.

We report here a novel t(3;14)(p13;q32) involving IGH, as shown by FISH, in three lymphoma cases. One of these cases was diagnosed as gastric MALT-type lymphoma, the remaining two cases as diffuse large B-cell lymphoma with a focal nodular growth pattern reminiscent of follicular lymphoma.

In order to identify the gene targeted by the t(3;14)(p13;q32) we performed FISH analysis of the first case and narrowed down the breakpoint to RP11-154H23 at 3p13 that showed a split signal on both derivative chromosomes. This BAC clone covers the FOXP1 gene. Using a pair of probes selected for the 5′ and 3′ ends of FOXP1, we demonstrated rearrangement of the gene by dual color FISH in the remaining two cases. An analysis of FOXP1 expression in present cases is being performed. FOXP1 (Forkhead box-P1) is a winged-helix transcription factor that acts as a transcriptional repressor. It is expressed in a wide variety of normal and neoplastic tissues, including lymphomas. FOXP1 has been shown to be expressed in normal activated B-cells using genomic-scale expression profiling, and in B-cells within and outside the germinal center by immunohistochemistry. Its physiological role in lymphocytes, however, is unclear. Recent studies showed that FOXP1 is strongly expressed in a subset of DLBCL. Interestingly, high expression of FOXP1 carries an independent prognostic significance, what suggests a possible role of the gene in the biology of this group of lymphoma. Although genomic rearrangements of FOXP1 have not been demonstrated so far in cancer, rearrangements of other members of FOX gene family in various pathological conditions have been reported. The involvement of FOXP1 in t(3;14)(p13;q32) found in two DLBCL cases indicates that this translocation may underlie a strong expression of FOXP1 in at least part of these lymphomas. Its rearrangement in a case of gastric lymphoma is intriguing, but additional investigations are required to find out whether t(3;14)(p13;q32) is a recurrent aberration in MALT lymphoma. Further molecular, immunophenotypic and clinical studies of the three cases with t(3;14)(p13;q32) are under progress.