title: IRF-4 suppresses BCR/ABL transformation of myeloid cells in a DNA binding-independent manner.
abstract: 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. 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 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.
authors: Rosenstiel Basic Medical Sciences Research Center and Department of Biology, Brandeis University, Waltham, Massachusetts 02454, USA.
authors: Seung-Hee
authors: SH
authors: Jo
authors: Ruibao
authors: R
authors: Ren
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004247:DNA / Q000235:genetics / Q000378:metabolism; D016044:Fusion Proteins, bcr-abl / Q000235:genetics / Q000378:metabolism*; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism* / Q000473:pathology; D017434:Protein Structure, Tertiary; D017384:Sequence Deletion; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D004247:DNA; D016044:Fusion Proteins, bcr-abl; D050835:Interferon Regulatory Factors; D025521:Tumor Suppressor Proteins; D000099218:Interferon Regulatory Factor-4