FOXR1 Activation in B-Cell Lymphoma

Several recurrent chromosomal aberrations targeting 11q23 have been described in diffuse large B-cell lymphoma (DLBCL). Here, we describe a novel fusion between RPS25 and FOXR1, two neighboring genes on 11q23 in the DLBCL cell line U-2932. RNAseq identified the fusion mRNA and genomic cloning localized the breakpoint to intron 2/3 of RPS25 and to the promoter region of FOXR1 (bp -3532). The cell line consists of two genetically distinct clones that represent subclones of the patients tumor.¹ We confirmed RPS25/FOXR1 fusion in the patients DNA and in one of the two cell line subclones suggesting that the fusion had occurred at some later stages of tumor development. Physiological FOXR1 expression is restricted to the early stages of embryogenesis. Ectopic expression as result of 11q23 intrachromosomal deletion-fusion had so far only been described in neuroblastoma.² In-frame fusions with the 5´ genes MLL and PAFAH1B2 led to the overexpression of FOXR1.² In accordance with the notion that also in DLBCL a constitutively expressed 5´ gene (RPS25) might be responsible for the ectopic expression of FOXR1, FOXR1 levels were 1000x higher in the fusion-positive than in the fusion-negative U-2932 subclone. Expression array analyses showed that the RPS25/FOXR1 positive U-2932 subclone had the highest FOXR1 expression level of 55 B-lymphoma cell lines tested, three log-scales higher than the average expression level. Santo et al.² reported that FOXR1 acts as negative regulator of fork-head box factor-mediated transcription and suggested a possible role in tumorigenesis. We describe for the first time that FOXR1 fusions also occur in lymphoma. In-silico analyses show that the aberrant expression of FOXR1 is rare, but recurrent in various forms of lymphoma. Given the potential oncogenic role of FOXR1, cell line U-2932 with one FOXR1-positive and one FOXR1-negative subclone appear to be a promising model for functional analysis of FOXR1-mediated cellular events.

1 Quentmeier H, Amini RM, Berglund M, et al. U-2932: two clones in one cell line, a tool for the study of clonal evolution. Leukemia. 2013;27(5):1155-1164.

2 Santo EE, Ebus ME, Koster J, et al. Oncogenic activation of FOXR1 by 11q23 intrachromosomal deletion-fusions in neuroblastoma. Oncogene 2012;31(12):1571-1581.