Genetic Rearrangements of FOXP1 Are Restricted to a Subset of Agressive B Cell Lymphoma with Extranodal Presentation.

In most mature B-cell non-Hodgkin lymphoma (NHL) chromosomal translocations result in the transcriptional deregulation of an oncogene by juxtaposing it to regulatory sequences of genes that are constitutively expressed in mature B cells, most often the Ig genes. Recently, a novel recurrent translocation t(3;14)(p13;q32) that results in deregulation of the FOXP1 forkhead transcription factor has been reported in a variety of B cell lymphoma.

Here we present the analysis of 275 B-cell NHL: 102 diffuse large B cell lymphoma (DLBCL) (49 nodal and 53 extranodal cases) 122 marginal zone lymphoma (MZL) from different localization (cutenous n= 9, salivary gland n= 13, pulmonary n=50, ocular adnexae n=36, thyroid n=8, gastric n=6), 30 follicular lymphoma (FL) and 21 mantle cell lymphoma (MCL). The presence of genetic aberrations involving the FOXP1 gene was studied by interphase fluorescence in situ hybridization (FISH) and FOXP1 protein expression - by immunohistochemistry using the JC12 monoclonal antibody.

In total, 5 of 275(2%) lymphoma were found to carry a chromosomal breakpoint within the FOXP1 gene. Further FISH studies indicated the presence of a FOXP1/IgH translocation in only 2 of these samples, suggesting the likely involvement of other translocation partner. All samples that harbored a FOXP1 breakpoint represented aggressive B cell lymphoma with proliferation fraction of 70–90% defined by the Ki 67% labeling pattern. Cytogenetic analysis and/or FISH suggested a presence of the complex chromosomal rearrangements. Four of 5 tumors presented at extranodal sites: gastro-intestinal tract (N=3); thyroid gland (N=1). All samples expressed B-cell markers and lacked CD5 and CD10 - a phenotype consistent with a marginal zone derivation. Interestingly, we failed to identify a FOXP1 breakpoint in any of the “true” low grade MZL in our series.

A gain of genomic material was found in 80 (29%) of these samples, indicated by detection of more than two FISH signals in a variable number of cells and/or cytogenetic data. In the vast majority of these cases trisomy 3 was further identified. All 5 samples that harbor FOXP1 chromosomal breakpoint showed strong nuclear labeling pattern when stained with JC12 monoclonal antibody. FOXP1 nuclear expression, in a variable number of the cells was detected in 95% of the cases with genomic gain/trisomy 3, however also in 40 % of the samples without evidence of any genetic aberrations in this locus, suggesting a range of mechanisms, regulating the FOXP1 expression.