Interferon regulatory factor-4 functions as a tumor suppressor

Interferon regulatory factor-4 (IRF-4) is transcription factor important for regulation of immune processes and hematopoietic development. Overexpression of IRF-4 is associated with oncogenic activity in mature B and T cell malignancies. Contrary to its function as an oncoprotein, reduced expression of IRF-4 has been demonstrated in several leukemic cell lines, in patients with chronic myelogenous leukemia (CML) and in patients with B cell acute lymphoblastic leukemia (B-ALL). This raises the possibility that downregulation of IRF-4 may be important to the pathogenesis of myeloid and lymphoid leukemias, suggesting a role for IRF-4 as a tumor suppressor.; IRF-4 is required for activation of B and T lymphocytes and the subsequent immune response. In addition to its unique activity, IRF-4 functions redundantly with IRF-8 to regulate maturation and function of immune cells. IRF-8 is a well established tumor suppressor. IRF-8 knockout mice develop a CML-like disease. We show that IRF-4 deficiency amplifies the CML-like disease that manifests in IRF-8 knockout mice, suggesting that IRF-4 may have overlapping activity with IRF-8 in suppressing CML. CML and a subset of B-ALL result from the chromosomal translocation, t(9;22)(q34,q11), which generates the fusion oncoprotein, BCR/ABL. We demonstrate that IRF-4 prolongs survival in a BCR/ABL induced CML mouse model. These results suggest that IRF-4 has tumor suppressor activity important for myeloid lineage leukemia.; Expression of IRF-4 is reduced in BCR/ABL expressing B lymphoid cells and in BCR/ABL positive B-ALL patients. IRF-4 expression is upregulated in response to therapy. This suggests that downregulation of IRF-4 may support progression of B-ALL. Our results show that IRF-4 inhibits BCR/ABL induced B cell transformation in vitro and in a BCR/ABL induced B-ALL mouse model. We also demonstrate that ectopic expression of IRF-4 negatively regulates proliferation in BCR/ABL transformed primary B cells.; Our results provide evidence that IRF-4 may function as tumor suppressor in the myeloid and lymphoid lineages. These studies may help elucidate new molecular pathways important to the pathogenesis of CML and B-ALL.