title: Interferon regulatory factor 4 attenuates Notch signaling to suppress the development of chronic lymphocytic leukemia.
abstract: Molecular pathogenesis of Chronic Lymphocytic Leukemia (CLL) is not fully elucidated. Genome wide association studies have linked Interferon Regulatory Factor 4 (IRF4) to the development of CLL. We recently established a causal relationship between low levels of IRF4 and development of CLL. However, the molecular mechanism through which IRF4 suppresses CLL development remains unclear. Deregulation of Notch signaling pathway has been identified as one of the most recurrent molecular anomalies in the pathogenesis of CLL. Yet, the role of Notch signaling as well as its regulation during CLL development remains poorly understood. Previously, we demonstrated that IRF4 deficient mice expressing immunoglobulin heavy chain Vh11 (IRF4-/-Vh11) developed spontaneous CLL with complete penetrance. In this study, we show that elevated Notch2 expression and the resulting hyperactivation of Notch signaling are common features of IRF4-/-Vh11 CLL cells. Our studies further reveal that Notch signaling is indispensable for CLL development in the IRF4-/-Vh11 mice. Moreover, we identify E3 ubiquitin ligase Nedd4, which targets Notch for degradation, as a direct target of IRF4 in CLL cells and their precursors. Collectively, our studies provide the first in vivo evidence for an essential role of Notch signaling in the development of CLL and establish IRF4 as a critical regulator of Notch signaling during CLL development.
authors.affiliation: Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Vipul
authors.initials: V
authors.lastname: Shukla
authors.affiliation: Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Ashima
authors.initials: A
authors.lastname: Shukla
authors.affiliation: Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Shantaram S
authors.initials: SS
authors.lastname: Joshi
authors.affiliation: Department of Genetics Cell Biology and Anatomy, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Runqing
authors.initials: R
authors.lastname: Lu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D016147:Genes, Tumor Suppressor; D055106:Genome-Wide Association Study; D006801:Humans; D050835:Interferon Regulatory Factors / Q000502:physiology*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D051883:Receptor, Notch2 / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D051883:Receptor, Notch2; D051880:Receptors, Notch; D000099218:Interferon Regulatory Factor-4; C497764:NOTCH2 protein, human
keywords: B1 cells; CLL; IRF4; Notch signaling