Loss of Tnk1/Kos1 in Mice Is Associated with B-Lymphomas Specifically DLBCL.

Abstract 3972

Poster Board III-908

The ubiquitously expressed nonreceptor tyrosine kinase (NRPTK) Tnk1/Kos1 (Thirty-eight negative kinase/Kinase of the embryonic stem cell) functions as a negative regulator of growth in both murine and human cells by suppressing the Ras-Raf1-MapK growth pathway. Since Tnk1 requires its intrinsic protein tyrosine kinase activity to suppress Ras activity and cell growth, the kinase domain is critical for its function and deletion by targeted homologous recombination leads to spontaneous tumor development in mice. To date, Tnk1/Kos1 is the only reported NRPTK that functions as a tumor suppressor in vivo, while other tyrosine kinases may be oncogenic when mutated or activated. While Tnk1 knockout mice may develop primary tumors in different tissues/organs, mainly B-cell lymphomas develop in Tnk1^-/- (80%, 47 of 60) and Tnk1^+/- (57%, 31 of 54) mice with similar characteristics of Diffuse Large B-Cell Lymphoma (DLBCL) and Burkitt Lymphoma types. Typically in lymphomas from Tnk1^+/- mice the intact wild type allele is epigenetically modified and silenced by promoter methylation. Importantly, the absence of Tnk1 occurs only in the tumor tissue but not in the adjacent uninvolved tissue. Now we find allelic loss with associated reduced expression of Tnk1 transcripts and protein in a cohort of human DLBCL patients. These data underscore the potential clinical relevance of Tnk1 in human hematological malignancies. Furthermore, the B-cell lymphomas that develop in the Tnk1 knockout mice express aberrantly high Ras activity indicating that unmutated Ras is a likely necessary effector of B-cell lymphoma development and survival. We also recently determined that the aberrantly high levels Ras activity in lymphoma (but not paired uninvolved lymphoid tissue) from mice results from a novel mechanism involving stabilization of the Grb2-Sos1 complex to maintain activated Ras in these tissues. Therefore, the Tnk1 knockout mouse provides a unique opportunity to test whether and how Tnk1 is involved in the development and/or maintenance of the B-cell lymphomas that develop in the absence of Ras mutation which may have clinical significance for patients with lymphoma.