IRF-4 Functions as a Tumor Suppressor in Early Stages of B Cell Development.

Interferon regulatory factor 4 (IRF-4) is a hematopoietic cell restricted transcription factor important for hematopoietic development and immune response regulation. IRF-4 is essential for mature B and T lymphocyte development, dendritic cell differentiation and some macrophage functions. It was also originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. Recent studies show that expression of IRF-4 is essential for the maintenance of multiple myeloma cells, making IRF-4 an attractive target for the development of cancer therapies. In addition to its role in late stages of lymphocyte development, IRF-4 functions redundantly with its closely related family member, IRF-8, to promote differentiation at the pre-B to immature B transition, apparently by repressing the pre-B cell receptor signaling and promoting light chain gene rearrangement. In contrast to its oncogenic properties, expression of IRF-4 is downregulated in BCR/ABL positive acute B-lymphoblastic leukemia (B-ALL) and is increased in response to imatinib, a selective BCR/ABL tyrosine kinase inhibitor. To assess the role of IRF-4 in the pathogenesis of BCR/ABL-positive B-ALL, we examined the effect of both loss of and forced expression of IRF-4 in BCR/ABL leukemogenesis using a mouse bone marrow transduction and transplantation model system. We found that BCR/ABL induced B-ALL significantly faster in IRF-4-deficient cells than control cells. On the other hand, forced expression of IRF-4 potently suppressed BCR/ABL transformation of bone marrow derived B lymphoid precursors in vitro and BCR/ABL induced B-ALL in vivo. These results provide evidence that IRF-4 functions as tumor suppressor in early B cell development and may allow elucidation of new molecular pathways significant to the pathogenesis of BCR/ABL positive B-ALL. In a parallel study, we have shown that IRF-4 functions as a tumor suppressor in myeloid lineage. The context dependent roles of IRF-4 in oncogenesis should raise caution in the development of cancer therapies targeting IRF-4. Further dissecting the mechanisms by which IRF-4 functions as an oncogene or a tumor suppressor gene is crucial for developing therapeutic strategies precisely targeting the IRF-4 oncogenic pathway as well as for developing therapeutic strategies taking advantage of the IRF-4 tumor suppressor pathway.