title: The Interferon Consensus Sequence Binding Protein (Icsbp/Irf8) Is Required for Termination of Emergency Granulopoiesis.
abstract: Emergency granulopoiesis occurs in response to infectious or inflammatory challenge and is a component of the innate immune response. Some molecular events involved in initiating emergency granulopoiesis are known, but termination of this process is less well defined. In this study, we found that the interferon consensus sequence binding protein (Icsbp/Irf8) was required to terminate emergency granulopoiesis. Icsbp is an interferon regulatory transcription factor with leukemia suppressor activity. Expression of Icsbp is decreased in chronic myeloid leukemia, and Icsbp(-/-) mice exhibit progressive granulocytosis with evolution to blast crisis, similar to the course of human chronic myeloid leukemia. In this study, we found aberrantly sustained granulocyte production in Icsbp(-/-) mice after stimulation of an emergency granulopoiesis response. Icsbp represses transcription of the genes encoding Fas-associated phosphatase 1 (Fap1) and growth arrest-specific 2 (Gas2) and activates genes encoding Fanconi C and F. After stimulation of emergency granulopoiesis, we found increased and sustained expression of Fap1 and Gas2 in bone marrow myeloid progenitor cells from Icsbp(-/-) mice in comparison with the wild type. This was associated with resistance to Fas-induced apoptosis and increased β-catenin activity in these cells. We also found that repeated episodes of emergency granulopoiesis accelerated progression to acute myeloid leukemia in Icsbp(-/-) mice. This was associated with impaired Fanconi C and F expression and increased sensitivity to DNA damage in bone marrow myeloid progenitors. Our results suggest that impaired Icsbp expression enhances leukemogenesis by deregulating processes that normally limit granulocyte expansion during the innate immune response.
authors.affiliation: From the Feinberg School of Medicine and.
authors.forename: Liping
authors.initials: L
authors.lastname: Hu
authors.affiliation: From the Feinberg School of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
authors.forename: Weiqi
authors.initials: W
authors.lastname: Huang
authors.affiliation: From the Feinberg School of Medicine and.
authors.forename: Elizabeth E
authors.initials: EE
authors.lastname: Hjort
authors.affiliation: From the Feinberg School of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612.
authors.forename: Ling
authors.initials: L
authors.lastname: Bei
authors.affiliation: From the Feinberg School of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611 and.
authors.forename: Leonidas C
authors.initials: LC
authors.lastname: Platanias
authors.affiliation: From the Feinberg School of Medicine and the Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois 60612 Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois 60611 and e-eklund@northwestern.edu.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eklund
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D006098:Granulocytes / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D019891:Leukopoiesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13 / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism; D000099185:Interferon Regulatory Factor-8
chemical_list: D050835:Interferon Regulatory Factors; D008840:Microfilament Proteins; D054595:Protein Tyrosine Phosphatase, Non-Receptor Type 13; D051176:beta Catenin; D019014:fas Receptor; D000099185:Interferon Regulatory Factor-8; C491899:Fas protein, mouse; C099165:Gas2 protein, mouse
keywords: CD95 (APO-1/Fas); calpain; gene expression; hematopoiesis; innate immunity