1. ¹Department of Biology, Boston University, Boston, MA, USA
2. ²Department of Medicine (Hematology & Oncology), University Hospital Schleswig-Holstein, Kiel, Germany
3. ³Institute of Human Genetics, University Hospital Schleswig-Holstein, Kiel, Germany
4. ⁴Department of Gynecology and Obstetrics, University Hospital Schleswig-Holstein, Kiel, Germany

Correspondence: Dr TD Gilmore, Department of Biology, Boston University, 5 Cummington Street, Boston, MA 02215, USA. E-mail: gilmore@bu.edu

⁵These authors contributed equally to this work

⁶Current address: BC Cancer Research Centre, Vancouver, BC, Canada

Received 17 November 2005; Revised 18 September 2006; Accepted 18 September 2006; Published online 30 October 2006.

Abstract

The human c-rel proto-oncogene (REL) encodes a subunit of the nuclear factor-kappaB (NF-B) transcription factor. In this report, we have identified an identical point mutation in two human B-cell lymphomas (follicular (FL) and mediastinal) that changes serine (Ser)525 (TCA) to proline (Pro) (CCA) within the REL transactivation domain. This mutation was not identified in a similarly sized cohort of healthy individuals. In the mediastinal B-cell lymphoma, the mutation in REL is of germ-line origin. In both tumors, the S525P mutant allele is over-represented. REL-S525P shows enhanced in vitro transforming activity in chicken spleen cells. REL-S525P has a reduced ability to activate the human manganese superoxide dismutase (MnSOD) promoter in A293 cells; however, the MnSOD protein shows increased expression in REL-S525P-transformed chicken spleen cells as compared to wild-type REL-transformed cells. Ser525 is a site for phosphorylation by IB kinase (IKK) in vitro. The S525P mutation reduces IKK- and tumor necrosis factor (TNF)-stimulated transactivation by a GAL4-REL protein. Furthermore, REL-S525P-transformed chicken spleen cells are more resistant to TNF-induced cell death than cells transformed by wild-type REL. These results suggest that the S525P mutation contributes to the development of human B-cell lymphomas by affecting an IKK-regulated transactivation activity of REL.