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PLoS One. 2014 Jan 9;9(1):e85851. doi: 10.1371/journal.pone.0085851. eCollection 2014.

Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.

Author information

1
Center for Human Genetics, KU Leuven, Leuven, Belgium.
2
Translational Cell and Tissue Research KU Leuven, Department of Pathology UZ Leuven, Leuven, Belgium.
3
Department of Pathology, University of Würzburg, Würzburg, Germany.
4
Mont-Godinne University Hospital, Yvoir, Belgium.
5
Virga Jesse Hospital, Hasselt, Belgium.
6
Center for Human Genetics, KU Leuven, Leuven, Belgium ; Center for the Biology of Disease, VIB, Leuven, Belgium.

Abstract

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.

PMID:
24416450
PMCID:
PMC3887110
DOI:
10.1371/journal.pone.0085851
[Indexed for MEDLINE]
Free PMC Article

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