The REL proto-oncogene encodes a transcription factor in the nuclear factor κB (NF-κB) family, and the activation of the REL protein can be controlled by subcellular localization. 1 The REL locus, located at chromosomal position 2p16, is amplified in many human B-cell lymphomas, 2 and overexpression of REL can transform chicken lymphoid cells in vitro. 3 Houldsworth et al4 recently reported on REL protein expression in a panel of diffuse large B-cell lymphomas (DLBCLs) with and without REL amplification. Using indirect immunofluorescence to assess subcellular localization of REL, these authors determined that DLBCLs with REL gene amplification did not have increased nuclear accumulation of REL protein compared with DLBCLs without REL gene amplification. This led these authors to conclude that REL protein activity is not involved in the development of DLBCLs with REL amplification, and that REL may not be the relevant oncogene in DLCBLs with amplifications of chromosomal region 2p16.

Based on the large amount of research that has been conducted on in vitro transformation of chicken lymphoid cells by v-Rel or more recently by human REL, we believe this is a faulty conclusion. First, by indirect immunofluorescence, v-Rel and human REL are largely cytoplasmic proteins in transformed chicken lymphoid cells. 3, 5 However, in electrophoretic mobility shift assays using nuclear extracts, there is clearly nuclear Rel DNA-binding activity in v-Rel–and REL-transformed chicken lymphoid cells, 3, 6 and v-Rel induces the expression of several κB site–containing target genes. 7 In addition, in these transformed cells, v-Rel and REL are continually shuttling through the nucleus, 3, 8 and one cannot detect this movement by a static immunofluorescence image. Moreover, this nuclear shuttling appears to be important for oncogenic activity, because if the nuclear shuttling of v-Rel is decreased by the addition of a strong nuclear export signal onto v-Rel, its transforming activity is reduced. 9 Thus, it is our contention that the REL immunofluorescence data of Houldsworth