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Background. The FOXP1 forkhead transcription factor is targeted by rare but recurrent translocations in B-NHL, particularly marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL). The most common is IGH-mediated t(3;14)(p14;q32) resulting in deregulation of FOXP1 transcription by regulatory sequences of IGH. Several translocations of FOXP1 involving non-IG loci have been described, but remain uncharacterized at the molecular level. Aims. This study aimed at genetic and molecular characterization of non-IG FOXP1 aberrations identified in 4 lymphoma cases. Methods. FISH with a panel of BAC probes was applied to map the affected breakpoints at 3p14/FOXP1 and 2q36, 3q11-q13 and 10q24. Expression of FOXP1 mRNA was analyzed by quantitative RT-PCR (QRT-PCR) with primers specific for exons 5-6, 7-8, 11-12, 14-15 and 17-18. Expression of FOXP1 protein was demonstrated by immunohistochemistry (IHC) with the JC12 antibody. Results. All 4 cases showed an aberrant expression of FOXP1 protein by IHC. Three of them displayed various 3p14 aberrations including t(2;3)(q36;p14) (C1) (MZL), inv(3)(p14;q11) (C2) (MZL) and t(3;10)(p14;q24) (C3) (CLL in Richter transformation). In one case of DLBCL (C4) a non-IG t(FOXP1) was detected by interphase FISH. In contrast to lymphomas with t(3;14) showing the 3p14 breakpoints in the 5’end of FOXP1, all cases with non-IG FOXP1 rearrangements displayed breakpoints in the 3’end of the gene. The reciprocal breakpoints were mapped within AP1S3 at 2q36 (C1), in a region at 3q11 lacking known genes (C2) and close to NFKB2 at 10q24 (C3). In C1, AP1S3 has an opposite transcriptional orientation to FOXP1, which precludes the role of its 5’ promoter in deregulation of FOXP1. Also the mechanism of FOXP1 overexpression in C2 with inv(3) affecting no known gene locus at 3q11 remains unknown. To check the hypothesis that non-IG translocations of FOXP1 result in an aberrant expression of variant FOXP1 transcripts, we performed exon-specific QRT-PCR analysis of two available cases (C2 and C4). As controls, we analyzed 2 cases with t(3;14) and 6 cases of DLBCL/MZL expressing FOXP1 but lacking FOXP1 rearrangements. These studies showed that both cases with t(3;14) expressed all analyzed coding exons (6-17) while cases with non-IGH translocations of FOXP1, as well as FOXP1+ DLBCL/MZL cases expressed sequences coded by exons 7-17, but not of exon 6. Conclusions. Our study demonstrates that the 3p14 breakpoints of non-IG FOXP1 rearrangements in lymphoma are clustered in the 3’end of the gene. Consequently, these aberrations result in expression of variant FOXP1 transcripts, likely encoding N-terminally truncated proteins, similar to potentially oncogenic smaller FOXP1 isoforms recently identified in ABC-DLBCL cell lines and primary DLBCLs. Which transcriptional regulatory elements are engaged to aberrantly express variant FOXP1 transcripts in these peculiar non-IG FOXP1 aberrations warrants further studies

Premature termination codon mutations in the von Willebrand factor gene are associated with allele-specific and position-dependent mRNA decay