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

• Published in: Blood 2005-03, Vol.105 (6), p.2535-2542
• Main Authors: Melzner, Ingo, Bucur, Alexandra Juliana, Brüderlein, Silke, Dorsch, Karola, Hasel, Cornelia, Barth, Thomas F.E., Leithäuser, Frank, Möller, Peter
• Format: Article
• Language: English
• Subjects: Alleles; Biological and medical sciences; Cell Line, Tumor; Chromosomes, Human, Pair 9 - genetics; Chromosomes, Human, Pair 9 - metabolism; Cyclin D1 - genetics; Cyclin D1 - metabolism; Gene Expression Regulation, Leukemic - genetics; Hematologic and hematopoietic diseases; Humans; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Janus Kinase 2; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, B-Cell - genetics; Lymphoma, B-Cell - metabolism; Mediastinal Neoplasms - genetics; Mediastinal Neoplasms - metabolism; Medical sciences; Mutation; Phosphorylation; Protein Processing, Post-Translational - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Repressor Proteins - genetics; Repressor Proteins - metabolism; Retinoblastoma Protein - genetics; Retinoblastoma Protein - metabolism; Signal Transduction - genetics; STAT5 Transcription Factor - genetics; STAT5 Transcription Factor - metabolism; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins - genetics; Suppressor of Cytokine Signaling Proteins - metabolism; Trisomy - genetics; Tumor Suppressor Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2004-09-3701

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 phosphorylated. However, JAK2 is not overexpressed at the protein level. On top, JAK2 protein turnover is even delayed. This unexpected finding coincides with a biallelic mutation of the suppressor of cytokine signaling-1 (SOCS-1) gene in this cell, which abrogates SOCS box function of the protein. Ectopic expression of wild-type (wt) SOCS-1 in MedB-1 leads to growth arrest and dramatic reduction of phospho-JAK2 and its downstream partner phospho–signal transducer and activator of transcription-5 (phospho-STAT5). Ultimately, the target gene cyclin D1 is repressed in transfectants while RB1, which is silenced in MedB-1, is induced. We conclude that, in MedB-1, action of phospho-JAK2 is sustained due to defective SOCS-1. Hence, SOCS-1 qualifies as a novel tumor suppressor. Of note, SOCS-1 mutations are also present in the parental tumor of MedB-1 and were detected in 9 of 20 PMBLs.