Abstract B16: Tumor suppressive functions by ATF2/7 transcription factors in a cMyc-driven B-cell lymphoma model

Abstract

Abstract ATF2 and the highly homologous ATF7 are members of the AP-1 transcription factor family which regulate expression of genes involved in development and stress response. In cancer, ATF2 has been reported to function both as a tumor suppressor and tumor promoter. The aim of the project was to investigate the possible roles of ATF2/7 in cMyc-driven B-cell lymphoma development and to characterize their interaction with the cMyc oncogene. Previously, cMyc, which is frequently deregulated in Burkitt's lymphoma (Rabbitts et al, 1984), was shown to prolong the half-life and induce phosphorylation of ATF2 (Miethe et al, 2001). In addition, the MAP kinase JNK and its substrate ATF2 are frequently found upregulated in B-cell lymphomas (Kersten et al, 2004; Gururajan et al, 2005). We established a mouse B-cell lymphoma model by crossing B-cell specific knockouts of Atf2/7 (Atf2ΔBC, Atf7−/−) with Eμ-Myc transgenic animals. Eμ-Myc mice express the cMyc proto-oncogene driven by the immunoglobulin heavy chain enhancer (Eμ) and develop B-cell lymphomas with high frequency. We compared timing of tumor onset between Eμ-myc, Atf2ΔBC, Atf7−/− Eμ-myc, Atf2ΔBC/+, Atf7−/−, and Eμ-myc, Atf7−/−. In addition, we derived cell lines fom Eμ-Myc-driven lymphomas and characterized growth, apoptosis, and drug sensitivity in the presence or absence of functional Atf2/7. Atf2 and its phosphorylated (activated) form were found to be upregulated in cells obtained from tumor samples from Eμ-Myc mice in comparison to normal B lymphocytes. Analysis of tumor-free survival showed that Eμ-myc, AtfΔBC, Atf7−/− develop B-cell lymphomas at significantly faster rates than controls. In vitro deletion of Atf2 in cell lines derived from cMyc-driven lymphomas resulted in a marked reduction in the basal levels of apoptosis. Furthermore, Atf2/7-deficient Eμ-myc tumor cells were significantly more resistant to genotoxic stress (e.g., doxorubicin) induced apoptosis. Gene expression analysis identified proapoptotic members of the Bcl-2 family as possible transcriptional targets of Atf2. In this study, we show a novel tumor suppressive role of ATF2 in cMyc-induced lymphomagenesis and suggest the potential functions of ATF2 in regulating programmed cell death. The results also imply that the evaluation of levels of activated ATF2 in clinical samples of B-cell lymphoma may give an indication of their sensitivity to chemotherapeutic agents. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B16.