Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in the MedB-1 mediastinal lymphoma line

Abstract

Primary mediastinal B-cell lymphoma (PMBL) is a well-defined subtype of diffuse large B-cell lymphoma. Molecular cytogenetics revealed frequent gains of 9p24. JAK2, mapping in this region, is presently regarded as a candidate oncogene because expression profiling showed high Janus kinase-2 (JAK2) transcript levels and JAK2 was found to be constitutively phosphorylated in mediastinal B-cell lymphomas. We confirm that in the MedB-1 mediastinal B-cell line, harboring a trisomy 9, JAK2 transcription is elevated and the product is highly

STAT5 represses BCL6 expression by binding to a regulatory region frequently mutated in lymphomas

“…In a number of hematopoietic lineages, we have demonstrated that STAT5 negatively regulates BCL6 expression by binding to region B. Interestingly, region B falls within a 'hot spot' of mutations, raising the possibility that these mutations could block STAT5 binding, and therefore, block repression, resulting in overexpression of BCL6. STAT5 is activated aberrantly in a variety of tumors, including DLBCL (Melzner et al, 2005), and may contribute to tumorigenesis by increasing expression of pro-survival genes. However, activation of STAT5 would be expected to repress BCL6 expression.…”

“…Constitutively active STAT5b, but not STAT5a, contributes to the tumorigenecity of squamous cell carcinoma of the head and neck (Leong et al, 2002;Xi et al, 2003), suggesting that STAT5b may be the oncogenic form of STAT5. Intriguingly, STAT5b is overexpressed in diffuse large B-cell lymphoma (DLBCL) (Shipp et al, 2002), and STAT5 is constitutively active in some DLBCL cell lines (Melzner et al, 2005), suggesting that both STAT5 and BCL6 may be important determinants in DLBCL pathogenesis.…”

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

“…Due to an in-frame mutation of one SOCS-1 allele in L428 and in L1236, the corresponding protein sequences lack five and four internal amino acid (aa) residues, respectively, so that the deletions are in close proximity within the SH2 domain leaving the SOCS box sequence unaffected. In contrast to MedB-1, however, recent data showed that L428 cells have no delayed JAK2 degradation arguing for the translation of the mutated SOCS-1 transcript in L428 into an at least partly functional protein (Melzner et al, 2005).…”

“…In various tumors, for example, multiple myeloma (Galm et al, 2003;Chim et al, 2004a), acute myeloid leukemia (Chen et al, 2003), mantle cell, and follicular lymphoma (Chim et al, 2004b), and in hepatocellular, pancreatic, ovarian, and breast carcinomas (Yoshikawa et al, 2001;Komazaki et al, 2004;Sutherland et al, 2004) the SOCS-1 gene was shown to be silenced by aberrant DNA methylation. In addition to the frequent epigenetic imprinting of tumor suppressor genes, we recently detected as a novel finding deletion mutations of SOCS-1 in primary mediastinal B-cell lymphoma (PMBL) predominantly leading to a truncation of the predicted SOCS-1 proteins (Melzner et al, 2005). Furthermore, we showed that the PMBL line MedB-1 has a biallelic mutation leading to abrogation of the SOCS box domain, and that PMBL line Karpas1106P has a biallelic deletion within chromosomal region 16p13.13 encompassing the SOCS-1 locus, hence, is SOCS-1 À/À (Melzner et al, 2006).…”

“…Moreover, ectopic expression of wild-type (wt) SOCS-1 in MedB-1 cells dramatically decreased the levels of phosphorylated JAK2 and STAT5, and significantly reduced the proliferation rate of MedB-1 cells (Melzner et al, 2005). Taking the above listed similarities between PMBL and cHL into account, it was obvious to investigate SOCS-1 status in cHL.…”