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Misregulation of REL, a nuclear factor-kappaB family transcription factor, has been implicated in several human lymphoid malignancies. REL has a conserved N-terminal DNA-binding/dimerization domain called the Rel homology domain (RHD) and a C-terminal transactivation domain (TAD). Here, we define the sequences (amino acids (aa) 323-422) between the RHD and TAD as a REL inhibitory domain (RID) because deletion of these sequences increases both REL transactivation and DNA binding. Furthermore, we have characterized two REL mRNA splice variants that encode proteins with alterations near RID: one lacking exon 9 sequences (aa 308-330; RELDelta9) and one with an exonized Alu fragment insertion of 32 aa after aa 307 (REL+Alu). Deletion of RID or exon 9-encoded sequences increases transactivation by GAL4-REL by approximately threefold. Moreover, deletion of RID or exon 9 sequences increases transactivation by full-length REL from certain kappaB site-containing promoters and increases DNA binding by REL. Deletion of RID does not affect REL's ability to transform chicken spleen cells. Reverse transcriptase-polymerase chain reaction analysis of mRNA from both primary lymphoma samples and several transformed tissue culture cell lines indicates that the RELDelta9 splice variant is preferentially expressed in lymphoma, suggesting that the REL transcript lacking exon 9 could serve as a marker for certain types of lymphoid tumors.

The suppressors of cytokine signaling (SOCS) are critically involved in the regulation of cellular proliferation, survival, and apoptosis via cytokine-induced JAK/STAT signaling. SOCS-1 silencing by aberrant DNA methylation contributes to oncogenesis in various B-cell neoplasias and carcinomas. Recently, we showed an alternative loss of SOCS-1 function due to deleterious SOCS-1 mutations in a major subset of primary mediastinal B-cell lymphoma (PMBL) and in the PMBL line MedB-1, and a biallelic SOCS-1 deletion in PMBL line Karpas1106P. For both cell lines our previous data demonstrated retarded JAK2 degradation and sustained phospho-JAK2 action leading to enhanced DNA binding of phospho-STAT5. Here, we analysed SOCS-1 in laser-microdissected Hodgkin and Reed-Sternberg (HRS) cells of classical Hodgkin lymphoma (cHL). We detected SOCS-1 mutations in HRS cells of eight of 19 cHL samples and in three of five Hodgkin lymphoma (HL)-derived cell lines by sequencing analysis. Moreover, we found a significant association between mutated SOCS-1 of isolated HRS cells and nuclear phospho-STAT5 accumulation in HRS cells of cHL tumor tissue (P < 0.01). Collectively, these findings support the concept that PMBL and cHL share many overlapping features, and that defective tumor suppressor gene SOCS-1 triggers an oncogenic pathway operative in both lymphomas.