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

<div><p>The transcription factor FOXP1 is implicated in the pathogenesis of B-cell lymphomas through chromosomal translocations involving either immunoglobulin heavy chain (<i>IGH</i>) locus or non-<i>IG</i> sequences. The former translocation, t(3;14)(p13;q32), results in dysregulated expression of <i>FOXP1</i> juxtaposed with strong regulatory elements of <i>IGH</i>. Thus far, molecular consequences of rare non-<i>IG</i> aberrations of <i>FOXP1</i> remain undetermined. Here, using molecular cytogenetics and molecular biology studies, we comprehensively analyzed four lymphoma cases with non-<i>IG</i> rearrangements of <i>FOXP1</i> and compared these with cases harboring t(3;14)(p13;q32)/<i>IGH-FOXP1</i> and FOXP1-expressing lymphomas with no apparent structural aberrations of the gene. Our study revealed that non-<i>IG</i> rearrangements of <i>FOXP1</i> 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 <i>FOXP1</i>, promiscuously fusing with coding and non-coding gene sequences at various reciprocal breakpoints (2q36, 10q24 and 3q11). The non-<i>IG</i> rearrangements of FOXP1, however, do not generate functional chimeric genes but commonly disrupt the full-length <i>FOXP1</i> 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)/<i>IGH-FOXP1</i> affects the 5′ untranslated region of <i>FOXP1</i> 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)/<i>IGH-FOXP1</i> activates expression of the FOXP1_FL protein with potent oncogenic activity, whereas the secondary non-<i>IG</i> rearrangements of <i>FOXP1</i> promote expression of the FOXP1_NT proteins, likely driving progression of disease.</p>