title: PU.1 cooperates with IRF4 and IRF8 to suppress pre-B-cell leukemia.
abstract: The Ets family transcription factor PU.1 and the interferon regulatory factor (IRF)4 and IRF8 regulate gene expression by binding to composite DNA sequences known as Ets/interferon consensus elements. Although all three factors are expressed from the onset of B-cell development, single deficiency of these factors in B-cell progenitors only mildly impacts on bone marrow B lymphopoiesis. Here we tested whether PU.1 cooperates with IRF factors in regulating early B-cell development. Lack of PU.1 and IRF4 resulted in a partial block in development the pre-B-cell stage. The combined deletion of PU.1 and IRF8 reduced recirculating B-cell numbers. Strikingly, all PU.1/IRF4 and ~50% of PU.1/IRF8 double deficient mice developed pre-B-cell acute lymphoblastic leukemia (B-ALL) associated with reduced expression of the established B-lineage tumor suppressor genes, Ikaros and Spi-B. These genes are directly regulated by PU.1/IRF4/IRF8, and restoration of Ikaros or Spi-B expression inhibited leukemic cell growth. In summary, we demonstrate that PU.1, IRF4 and IRF8 cooperate to regulate early B-cell development and to prevent pre-B-ALL formation.
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S H M
authors.initials: SH
authors.lastname: Pang
authors.affiliation: The Institute of Molecular Pathology, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Minnich
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: P
authors.initials: P
authors.lastname: Gangatirkar
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
authors.forename: Z
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: The Institute of Molecular Pathology, Vienna, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Ebert
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: G
authors.initials: G
authors.lastname: Song
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: R A
authors.initials: RA
authors.lastname: Dickins
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: L M
authors.initials: LM
authors.lastname: Corcoran
authors.affiliation: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: C G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: The Institute of Molecular Pathology, Vienna, Austria.
authors.forename: M
authors.initials: M
authors.lastname: Busslinger
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: N D
authors.initials: ND
authors.lastname: Huntington
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S L
authors.initials: SL
authors.lastname: Nutt
authors.affiliation: Molecular Immunology Department, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: S
authors.initials: S
authors.lastname: Carotta
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D005786:Gene Expression Regulation; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000502:physiology*; D038041:Lymphopoiesis; D051379:Mice; D018345:Mice, Knockout; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000517:prevention & control; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics / Q000502:physiology*; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4
chemical_list: D050835:Interferon Regulatory Factors; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D000099185:Interferon Regulatory Factor-8; D000099232:Proto-Oncogene Protein Spi-1; D000099218:Interferon Regulatory Factor-4