Abstract 5070: Identification of DKK2 as a candidate gene that facilitates tumor reoccurrence upon MYC inactivation

Abstract

Abstract The MYC oncogene is prevalently activated in human hematopoietic cancers, especially T-cell acute lymphoblastic leukemia (T-ALL) and Burkitt's lymphoma. Utilizing the Tet-system to generate a conditional model of MYC-induced T-ALL, our laboratory has demonstrated that MYC inactivation induces sustained tumor regression. However, after prolonged MYC inactivation some tumors eventually escape MYC dependence and reoccur. Our results support the hypothesis that tumors escape complete dependence on MYC by acquiring additional genetic or epigenetic changes, leading to altered gene function that may substitute totally or partially for MYC. Specifically, using Spectral Karyotypic Analysis (SKY) and array Comparative Genomic Hybridization (aCGH) we have obtained evidence that the Wnt/ β-catenin related gene, DKK2, may play a role in the mechanism by which tumors escape dependence upon MYC. We demonstrate DKK2 facilitates the ability of MYC-driven lymphomas to reoccur even in the presence of sustained oncogene inactivation. We have evidence that cellular context may play a pivotal role in DKK2's ability to aid tumor reoccurrence. Our data also suggest a mechanism by which DKK2 functions, alone or in conjunction with other Wnt/β-catenin pathway members, to maintain tumorigenesis or facilitate tumor reoccurrence in murine and human MYC-driven tumors in the presence of sustained MYC inactivation. Discovering that DKK2 overexpression may aid in lymphoma reoccurrence is a highly novel finding as DKK2 has never been implicated as an oncogene in lymphoma. Results presented here provide critical new insights into the mechanism by which MYC-driven cancers may obtain chemotherapeutic resistance and reoccur even in the presence of sustained drug therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5070.