Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated Isoforms of FOXP1
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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 withThe 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 59 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.…
Autor(en): | 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 |
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URN: | urn:nbn:de:bvb:20-opus-117679 |
Dokumentart: | Artikel / Aufsatz in einer Zeitschrift |
Institute der Universität: | Medizinische Fakultät / Pathologisches Institut |
Sprache der Veröffentlichung: | Englisch |
Titel des übergeordneten Werkes / der Zeitschrift (Englisch): | PLOS ONE |
ISSN: | 1932-6203 |
Erscheinungsjahr: | 2014 |
Band / Jahrgang: | 9 |
Heft / Ausgabe: | 1 |
Seitenangabe: | e85851 |
Originalveröffentlichung / Quelle: | PLoS ONE 9(1): e85851. doi:10.1371/journal.pone.0085851 |
DOI: | https://doi.org/10.1371/journal.pone.0085851 |
PubMed-ID: | https://pubmed.ncbi.nlm.nih.gov/24416450 |
Allgemeine fachliche Zuordnung (DDC-Klassifikation): | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Freie Schlagwort(e): | acute lymphoblastic leukemia; cardiomyocyte proliferation; chromosomal aberration; down regulation; gene; lymphoid-tissue lymphomas; malt lymphoma; poor prognosis; prostate cancer; transcription factor FOXP1 |
Datum der Freischaltung: | 24.08.2015 |
Lizenz (Deutsch): | CC BY: Creative-Commons-Lizenz: Namensnennung |