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

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Rouhigharabaei, Leila Ferreiro, Julio Finalet Tousseyn, Thomas Van Der Krogt, Jo-Anne Put, Natalie Graux, Carlos [UCL] Wlodarska, Iwona

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 (FOXP1NT), 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 (FOXP1FL). RNA-sequencing of a few lymphoma cases expressing FOXP1NT and FOXP1FL 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 FOXP1NT, 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 FOXP1FL protein with potent oncogenic activity, whereas the secondary non-IG rearrangements of FOXP1 promote expression of the FOXP1NT proteins, likely driving progression of disease.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2014
Language Anglais
Journal information "PloS One" - Vol. 9, no. 1, p. e85851 [1-12] (2014)
Peer reviewed yes
Publisher Public Library of Science ((United States) San Francisco, CA)
e-issn 1932-6203
Publication status Publié
Affiliations UCL - (MGD) Service d'hématologie
UCL - SSS/IREC/MONT - Pôle Mont Godinne
Keywords Lymphomas ; Forkhead box ; Gene targeting ; Translocations ; Carcinogenesis
Links
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Bibliographic reference Rouhigharabaei, Leila ; Ferreiro, Julio Finalet ; Tousseyn, Thomas ; Van Der Krogt, Jo-Anne ; Put, Natalie ; et. al. Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1. In: PloS One, Vol. 9, no. 1, p. e85851 [1-12] (2014)
Permanent URL http://hdl.handle.net/2078.1/144859