title: Increased leukocyte survival and accelerated onset of lymphoma in the absence of MCL-1 S159-phosphorylation.
abstract: The antiapoptotic BCL-2 protein MCL-1, which opposes mitochondrial outer membrane permeabilization, was shown to have a crucial role in the survival of hematopoietic cells. We have previously shown that, upon loss of phosphatidylinositol 3-kinase signaling, S159 of MCL-1 is phosphorylated by glycogen synthase kinase-3 (GSK-3), earmarking MCL-1 for enhanced ubiquitylation and degradation. In this study, we introduced MCL-1(wt) or the phosphorylation-deficient mutant MCL-1(S159A) in mouse BM cells, followed by adoptive transfer to recipient mice. Mice expressing MCL-1(S159A) exhibited significantly elevated white blood cell and lymphocyte counts, whereas no effect was observed on the distribution of T and B lymphocyte subsets or the numbers of monocytes, red blood cells or platelets. Expression of MCL-1(S159A) in Eμ-Myc transgenic bone marrow significantly accelerated the onset of disease, and these mice displayed increased spleen weights compared with Eμ-Myc/MCL-1(wt) mice. Our data demonstrate that the absence of MCL-1 S159 phosphorylation provides a survival advantage for hematopoietic cells in vivo and facilitates oncogenesis.
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: S E
authors.initials: SE
authors.lastname: Lindner
authors.affiliation: Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Wissler
authors.affiliation: Department of Molecular Hematology, Center for Clinical Research, University Hospital, Freiburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Gründer
authors.affiliation: Institute of Pathology, University Medical Centre Freiburg, Freiburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Aumann
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Ottina
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: L
authors.initials: L
authors.lastname: Peintner
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany [3] Spemann Graduate School for Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Brauns-Schubert
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Faculty of Biology, Albert-Ludwigs-University Freiburg, Freiburg, Germany [3] Spemann Graduate School for Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Preiss
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Herzog
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Spemann Graduate School for Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany [3] BIOSS, Centre for Biological Signaling Studies, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Borner
authors.affiliation: Institut Cochin, INSERM U1016/CNRS UMR 8104, Université Paris Descartes, Rue Méchain, Paris.
authors.forename: C
authors.initials: C
authors.lastname: Charvet
authors.affiliation: Division of Developmental Immunology, BIOCENTER, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Villunger
authors.affiliation: Department of Molecular Hematology, Center for Clinical Research, University Hospital, Freiburg, Germany.
authors.forename: H L
authors.initials: HL
authors.lastname: Pahl
authors.affiliation: 1] Institute of Molecular Medicine and Cell Research, Albert-Ludwigs-University Freiburg, Freiburg, Germany [2] Spemann Graduate School for Biology and Medicine (SGBM), Albert-Ludwigs-University Freiburg, Freiburg, Germany [3] BIOSS, Centre for Biological Signaling Studies, Freiburg, Germany.
authors.forename: U
authors.initials: U
authors.lastname: Maurer
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007962:Leukocytes / Q000378:metabolism* / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology; D008223:Lymphoma / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D013154:Spleen / Q000166:cytology
chemical_list: C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D049452:Green Fluorescent Proteins