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The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain ( IGH ) locus or non- IG  sequences. The former translocation, t(3;14)(p13;q32), results in dysregulated expression of  FOXP1  juxtaposed with strong regulatory elements of  IGH . Thus far, molecular consequences of rare non- IG  aberrations of  FOXP1  remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non- IG  rearrangements of  FOXP1  and compared these with cases harboring t(3;14)(p13;q32)/ IGH-FOXP1  and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non- IG  rearrangements of  FOXP1  are usually acquired during clinical course of various lymphoma subtypes, including diffuse large B cell lymphoma, marginal zone lymphoma and chronic lymphocytic leukemia, and correlate with a poor prognosis. Importantly, these aberrations constantly target the coding region of  FOXP1 , promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non- IG  rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length  FOXP1  transcript leading to an aberrant expression of N-truncated FOXP1 isoforms (FOXP1 NT) , as shown by QRT-PCR and Western blot analysis. In contrast, t(3;14)(p13;q32)/ IGH-FOXP1  affects the 5′ untranslated region of  FOXP1  and results in overexpress the full-length FOXP1 protein (FOXP1 FL ). RNA-sequencing of a few lymphoma cases expressing FOXP1 NT  and FOXP1 FL  detected neither FOXP1-related fusions nor FOXP1 mutations. Further bioinformatic analysis of RNA-sequencing data retrieved a set of genes, which may comprise direct or non-direct targets of FOXP1 NT , potentially implicated in disease progression. In summary, our findings point to a dual mechanism through which FOXP1 is implicated in B-cell lymphomagenesis. We hypothesize that the primary t(3;14)(p13;q32)/ IGH-FOXP1  activates expression of the FOXP1 FL  protein with potent oncogenic activity, whereas the secondary non- IG  rearrangements of  FOXP1  promote expression of the FOXP1 NT  proteins, likely driving progression of disease.

Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated Isoforms of FOXP1