Expression and Oncogenic Role of Brk (PTK6/Sik) Protein Tyrosine Kinase in Lymphocytes

Monika Kasprzycka^*, Miroslaw Majewski^*, Zhi-Jong Wang^*, Andrzej Ptasznik, Maria Wysocka^¶, Qian Zhang^*, Michal Marzec^*, Phyllis Gimotty^||, Mark R. Crompton^** and Mariusz A. Wasik^*

From the Departments of Pathology and Laboratory Medicine,^* Medicine, Dermatology,^¶ and Biostatistics and Epidemiology,|| University of Pennsylvania, Philadelphia, Pennsylvania; the Department of Clinical Immunology, Warsaw Medical University, Warsaw, Poland; the Department of Hematology, Institute of Hematology and Blood Transfusion, Warsaw, Poland; and the School of Biological Sciences,^*^* Royal Holloway University of London, Surrey, United Kingdom

Tyrosine kinases play a fundamental role in cell proliferation,survival, adhesion, and motility and have also been shown tomediate malignant cell transformation. Here we describe constitutiveexpression of the protein tyrosine kinase Brk in a large proportionof cutaneous T-cell lymphomas and other transformed T- and B-cellpopulations. The kinase is expressed in the nuclear localizationand activated state. Brk expression was also induced in normalT cells on their activation. Introduced expression of the Brkgene resulted in markedly diminished cytokine and growth factordependence of transfected BaF3 lymphocytes in regard to theirin vitro proliferation and survival. Brk also conferred in vivooncogenicity on the BaF3 cells. siRNA-mediated inhibition ofthe endogenous Brk in malignant T cells diminished their growthand survival capacity. These findings document inducible expressionof Brk in normal T lymphocytes and persistent expression ofthe activated kinase in malignant T and B cells. Furthermore,our results indicate that Brk may play a key role in lymphomagenesis,hence identifying the kinase as a potential therapeutic targetin lymphomas.