Submitted October 11, 2007
Accepted July 19, 2008
IRF-4 functions as a tumor suppressor in early B-cell development
Jaime Acquaviva, Xiaoren Chen, and Ruibao Ren*
Rosenstiel Basic Medical Sciences Research Center, Brandeis University, Waltham, Massachusetts 02454, United States
* Corresponding author; email: ren{at}brandeis.edu.
IRF-4 is a hematopoietic cell-restricted transcription factor important for hematopoietic development and immune response regulation. It was also originally identified as the product of a proto-oncogene involved in chromosomal translocations in multiple myeloma. In contrast to its oncogenic function in late stages of B lymphopoiesis, expression of IRF-4 is downregulated in certain myeloid and early B-lymphoid malignancies. In this study we found that the IRF-4 protein levels are increased in lymphoblastic cells transformed by the BCR/ABL oncogene in response to BCR/ABL tyrosine kinase inhibitor imatinib. We further found that IRF-4-deficiency enhances BCR/ABL transformation of B-lymphoid progenitors in vitro and accelerates disease progression of BCR/ABL induced acute B-lymphoblastic leukemia (B-ALL) in mice, while forced expression of IRF-4 potently suppresses BCR/ABL transformation of B-lymphoid progenitors in vitro and BCR/ABL induced B-ALL in vivo. Further analysis showed that IRF-4 inhibits growth of BCR/ABL+ B-lymphoblasts primarily through negative regulation of cell cycle progression. These results demonstrate that IRF-4 functions as tumor suppressor in early B-cell development and may allow elucidation of new molecular pathways significant to the lymphoid leukemogenesis by BCR/ABL. The context dependent roles of IRF-4 in oncogenesis should be an important consideration in developing cancer therapies targeting IRF-4.
