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

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...

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Autores principales:	Leila Rouhigharabaei, Julio Finalet Ferreiro, Thomas Tousseyn, Jo-Anne van der Krogt, Natalie Put, Eugenia Haralambieva, Carlos Graux, Brigitte Maes, Carmen Vicente, Peter Vandenberghe, Jan Cools, Iwona Wlodarska
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2014
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/6fdfd1660fbb45909fdf610a1b8dc7aa
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spelling	oai:doaj.org-article:6fdfd1660fbb45909fdf610a1b8dc7aa2021-11-18T08:38:06ZNon-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.1932-620310.1371/journal.pone.0085851https://doaj.org/article/6fdfd1660fbb45909fdf610a1b8dc7aa2014-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/24416450/pdf/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Leila RouhigharabaeiJulio Finalet FerreiroThomas TousseynJo-Anne van der KrogtNatalie PutEugenia HaralambievaCarlos GrauxBrigitte MaesCarmen VicentePeter VandenbergheJan CoolsIwona WlodarskaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 9, Iss 1, p e85851 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Leila Rouhigharabaei Julio Finalet Ferreiro Thomas Tousseyn Jo-Anne van der Krogt Natalie Put Eugenia Haralambieva Carlos Graux Brigitte Maes Carmen Vicente Peter Vandenberghe Jan Cools Iwona Wlodarska Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
description	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.
format	article
author	Leila Rouhigharabaei Julio Finalet Ferreiro Thomas Tousseyn Jo-Anne van der Krogt Natalie Put Eugenia Haralambieva Carlos Graux Brigitte Maes Carmen Vicente Peter Vandenberghe Jan Cools Iwona Wlodarska
author_facet	Leila Rouhigharabaei Julio Finalet Ferreiro Thomas Tousseyn Jo-Anne van der Krogt Natalie Put Eugenia Haralambieva Carlos Graux Brigitte Maes Carmen Vicente Peter Vandenberghe Jan Cools Iwona Wlodarska
author_sort	Leila Rouhigharabaei
title	Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
title_short	Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
title_full	Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
title_fullStr	Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
title_full_unstemmed	Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
title_sort	non-ig aberrations of foxp1 in b-cell malignancies lead to an aberrant expression of n-truncated isoforms of foxp1.
publisher	Public Library of Science (PLoS)
publishDate	2014
url	https://doaj.org/article/6fdfd1660fbb45909fdf610a1b8dc7aa
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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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