title: IRF4 is a suppressor of c-Myc induced B cell leukemia.
abstract: Interferon regulatory factor 4 (IRF4) is a critical transcriptional regulator in B cell development and function. We have previously shown that IRF4, together with IRF8, orchestrates pre-B cell development by limiting pre-B cell expansion and by promoting pre-B cell differentiation. Here, we report that IRF4 suppresses c-Myc induced leukemia in EμMyc mice. Our results show that c-Myc induced leukemia was greatly accelerated in the IRF4 heterozygous mice (IRF4(+/-)Myc); the average age of mortality in the IRF4(+/-)Myc mice was only 7 to 8 weeks but was 20 weeks in the control mice. Our results show that IRF4(+/-)Myc leukemic cells were derived from large pre-B cells and were hyperproliferative and resistant to apoptosis. Further analysis revealed that the majority of IRF4(+/-)Myc leukemic cells inactivated the wild-type IRF4 allele and contained defects in Arf-p53 tumor suppressor pathway. p27(kip) is part of the molecular circuitry that controls pre-B cell expansion. Our results show that expression of p27(kip) was lost in the IRF4(+/-)Myc leukemic cells and reconstitution of IRF4 expression in those cells induced p27(kip) and inhibited their expansion. Thus, IRF4 functions as a classical tumor suppressor to inhibit c-Myc induced B cell leukemia in EμMyc mice.
authors.affiliation: Department of Genetics, Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
authors.forename: Simanta
authors.initials: S
authors.lastname: Pathak
authors.forename: Shibin
authors.initials: S
authors.lastname: Ma
authors.forename: Long
authors.initials: L
authors.lastname: Trinh
authors.forename: James
authors.initials: J
authors.lastname: Eudy
authors.forename: Kay-Uwe
authors.initials: KU
authors.lastname: Wagner
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
authors.forename: Runqing
authors.initials: R
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D050835:Interferon Regulatory Factors / Q000378:metabolism*; D015448:Leukemia, B-Cell / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D018655:Lymphocyte Count; D051379:Mice; D009368:Neoplasm Transplantation; D054448:Precursor Cells, B-Lymphoid / Q000378:metabolism / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D050760:Cyclin-Dependent Kinase Inhibitor p27; D007075:Immunoglobulin M; D050835:Interferon Regulatory Factors; D017493:Leukocyte Common Antigens; D016271:Proto-Oncogene Proteins c-myc; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000099218:Interferon Regulatory Factor-4