IRF-4 Suppresses BCR/ABL Transformation of Myeloid Cells in a DNA-Binding Independent Manner

Abstract 1404

Interferon regulatory factor 4 (IRF-4) is essential for B and T cell development and immune response regulation, and has both nuclear and cytoplasmic functions. IRF-4 was originally identified as a proto-oncogene resulting from a t(6;14) chromosomal translocation in multiple myeloma and its expression was shown to be essential for multiple myeloma cell survival. However, we have previously shown that IRF-4 functions as a tumor suppressor in the myeloid lineage and in early stages of B cell development. The finding of IRF-4 functioning as a tumor suppressor raises caution for developing therapies aiming to downregulate IRF-4. Further studies on the mechanisms by which IRF-4 functions as an oncoprotein and as a tumor suppressor are necessary to develop improved therapies for malignancies involving IRF-4. In this study, we found that IRF-4 suppresses BCR/ABL transformation of myeloid cells. To gain insight into the molecular pathways that mediate IRF-4 tumor suppressor function, we performed a structure-function analysis of IRF-4 as a suppressor of BCR/ABL transformation. We found that the DNA binding domain deletion mutant of IRF-4, which is localized only in the cytoplasm, is still able to inhibit BCR/ABL transformation of myeloid cells. IRF-4 also functions as a tumor suppressor in bone marrow cells deficient in MyD88, an IRF-4 interacting protein found in the cytoplasm. However, IRF-4's tumor suppressor activity is lost in IRF association domain (IAD) deletion mutants. These results demonstrate that IRF-4 suppresses BCR/ABL transformation by a novel cytoplasmic function involving its IAD domain and suggest that the oncogenic and tumor suppressor functions of IRF-4 involve distinct pathways.