title: Non-IG aberrations of FOXP1 in B-cell malignancies lead to an aberrant expression of N-truncated isoforms of FOXP1.
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.
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Leila
authors.initials: L
authors.lastname: Rouhigharabaei
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Julio
authors.initials: J
authors.lastname: Finalet Ferreiro
authors.affiliation: Translational Cell and Tissue Research KU Leuven, Department of Pathology UZ Leuven, Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Tousseyn
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Jo-Anne
authors.initials: JA
authors.lastname: van der Krogt
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Natalie
authors.initials: N
authors.lastname: Put
authors.affiliation: Department of Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Haralambieva
authors.affiliation: Mont-Godinne University Hospital, Yvoir, Belgium.
authors.forename: Carlos
authors.initials: C
authors.lastname: Graux
authors.affiliation: Virga Jesse Hospital, Hasselt, Belgium.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maes
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium ; Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Carmen
authors.initials: C
authors.lastname: Vicente
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: Vandenberghe
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium ; Center for the Biology of Disease, VIB, Leuven, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Cools
authors.affiliation: Center for Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Iwona
authors.initials: I
authors.lastname: Wlodarska
mesh_terms: D019457:Chromosome Breakage; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks / Q000235:genetics; D050438:Genes, Immunoglobulin Heavy Chain; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D016393:Lymphoma, B-Cell / Q000235:genetics* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D017423:Sequence Analysis, RNA
chemical_list: C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D020033:Protein Isoforms; D012333:RNA, Messenger; D012097:Repressor Proteins; D046988:Proteasome Endopeptidase Complex