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Blood, 15 March 2005, Vol. 105, No. 6, pp. 2535-2542.
Prepublished online as a Blood First Edition Paper on November 30, 2004; DOI 10.1182/blood-2004-09-3701.
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Submitted September 24, 2004
Accepted November 17, 2004
Biallelic mutation of SOCS-1 impairs JAK2 degradation and sustains phospho-JAK2 action in MedB-1 mediastinal lymphoma line
Ingo Melzner, Alexandra J Bucur, Silke Bruderlein, Karola Dorsch, Cornelia Hasel, Thomas F Barth, Frank Leithauser, and Peter Moller*
Department of Pathology, University of Ulm, Ulm, Germany
* Corresponding author; email: peter.moeller{at}medizin.uni-ulm.de.
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 since expression profiling showed high 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, harbouring a trisomy 9, JAK2 transcription is elevated and the product is highly phosphorylated. However, JAK2 is not over-expressed at the protein level. On top, JAK2 protein turnover is even delayed. This unexpected finding coincides with a biallelic mutation of the SOCS-1 gene in this cell, which abrogates SOCS box function of the protein. Ectopic expression of wt-SOCS-1 in MedB-1 leads to growth arrest, dramatic reduction of phospho-JAK2 and its downstream partner 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 PMBL.
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