The long term objectives of this research proposal are to define the oncogene-induced pathways that promote myeloid cell leukemogenesis. Although the oncoprotein c-Myc, which promotes cell cycle progression, is constitutively activated in many leukemia and lymphomas, it also is a potent inducer of apoptosis. Preliminary investigations into Myc-induced apoptosis have suggested that Myc influences the expression of proteins that regulate apoptosis. Myc selectively suppresses Bcl-2, an anti-apoptotic protein, in immortal IL-3-dependent myeloid cell lines, whereas Myc induces the tumor suppressors p19ARF and p53 in fibroblasts. Creating a mouse model of myeloid leukemia by generating a myeloid cell-specific Myc transgenic mouse will provide an essential resource to test our hypothesis that a relationship exists between myc-induced apoptosis and transformation. The myeloid cell-specific Myc Tg mice crossed to Bcl-2, Bax-, p19ARF-, and p53-null mice will elucidate the contribution these proteins have to Myc-induced myeloid cell death and tumorigenesis. These studies will further our understanding of Myc-induced myeloid cell transformation and how apoptotic pathways influence this process.
| Eischen, Christine M; Rehg, Jerold E; Korsmeyer, Stanley J et al. (2002) Loss of Bax alters tumor spectrum and tumor numbers in ARF-deficient mice. Cancer Res 62:2184-91 |
| Eischen, C M; Packham, G; Nip, J et al. (2001) Bcl-2 is an apoptotic target suppressed by both c-Myc and E2F-1. Oncogene 20:6983-93 |
| Eischen, C M; Woo, D; Roussel, M F et al. (2001) Apoptosis triggered by Myc-induced suppression of Bcl-X(L) or Bcl-2 is bypassed during lymphomagenesis. Mol Cell Biol 21:5063-70 |
| Eischen, C M; Roussel, M F; Korsmeyer, S J et al. (2001) Bax loss impairs Myc-induced apoptosis and circumvents the selection of p53 mutations during Myc-mediated lymphomagenesis. Mol Cell Biol 21:7653-62 |
