Biallelic Mutation of SOCS-1 Impairs JAK2 Degradation and Sustains Phospho-JAK2 Action in MedB-1 Mediastinal Lymphoma Line.

Mediastinal B-cell lymphoma 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 constitutive phosphorylated in mediastinal B-cell lymphomas. We confirm that in MedB-1 mediastinal 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 perpetuates 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, at least in MedB-1, JAK2 is not a constitutive oncogene but secondarily accumulates in its active form due to defective SOCS-1. Hence, SOCS-1 qualifies as a novel tumor suppressor. Of note, the biallelic SOCS-1 mutation is also present in the parental tumor of MedB-1.