TY  - JOUR
A1  - Rouhigharabaei, Leila
A1  - Ferreiro, Julio Finalet
A1  - Tousseyn, Thomas
A1  - van der Krogt, Jo-Anne
A1  - Put, Natalie
A1  - Haralambieva, Eugenia
A1  - Graux, Carlos
A1  - Maes, Brigitte
A1  - Vicente, Carmen
A1  - Vandenberghe, Peter
A1  - Cools, Jan
A1  - Wlodarska, Iwona
T1  - Non-IG Aberrations of FOXP1 in B-Cell Malignancies Lead to an Aberrant Expression of N-Truncated Isoforms of FOXP1
T2  - PLOS ONE
N2  - 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 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.
KW  - lymphoid-tissue lymphomas
KW  - acute lymphoblastic leukemia
KW  - transcription factor FOXP1
KW  - cardiomyocyte proliferation
KW  - chromosomal aberration
KW  - prostate cancer
KW  - down regulation
KW  - poor prognosis
KW  - malt lymphoma
KW  - gene
Y1  - 2014
UR  - https://opus.bibliothek.uni-wuerzburg.de/frontdoor/index/index/docId/11767
UR  - https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-117679
SN  - 1932-6203
VL  - 9
IS  - 1
ER  -