Targeting the IRF2 Transcription Factor To Inhibit Leukaemic Cell Growth.

Activating mutations of the Ras genes occur at high frequency in acute myeloid leukemia (AML). We have previously shown that expression of mutant N-ras(N-ras^m) in murine hematopoietic stem cells is sufficient to induce a myeloid malignancy that resembles human AML(Mackenzie et al. Blood, 1999, 93, 2043–2056). In a ’humanised’ NOD/SCID mouse model N-ras^m induced a pre-leukemic condition characterised by myeloid proliferation of human hematopoietic progenitor cells in the bone marrow of recipient mice (Shen et al. Exp. Hematol., 2004, 32: 852–860). Even though Ras usually acts as a dominant transforming oncogene, in primary cells and some cancer cell lines, Ras inhibits cell growth. We have previously shown that ectopic expression of N-ras^m in leukemia U937 and K562 cells leads to growth suppression (Passioura et al. Cancer Res. 2005, 65, 797–804). The expression profile induced by N-ras^m in these cells included the up-regulation of transcription factor Interferon Regulatory Factor1 (IRF1) and activation of cdk inhibitor p21^WAF. IRF1 was previously defined as a tumour suppressor, and as such is a target of oncogenic mutations in AML. Antisense suppression of IRF1 prevented N-ras^m induced growth suppression and up-regulation of p21^WAF1. These results defined a novel tumour suppressive response to oncogenic N-ras^m in leukemia cells. A retroviral cDNA library screen for genes that counteract N-ras^m-induced growth suppression identified the gene for the Interferon Regulatory Factor2 (IRF2), and as confirmation of the screen, over-expression of IRF2 in leukemia U937 cells acted to inhibit N-ras^m-induced growth suppression (