title: Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation.
abstract: Recent investigations indicate that epigenetic regulators act at the initial step of myeloid leukemogenesis by forming preleukemic hematopoietic stem cells (HSCs), which possess the increased self-renewal potential but retain multidifferentiation ability, and synergize with genetic abnormalities in later stages to develop full-blown acute myeloid leukemias. However, it is still unknown whether this theory is applicable to other malignancies. In this study, we demonstrate that lysine-specific demethylase 1 (LSD1) overexpression is a founder abnormality for the development of T-cell lymphoblastic leukemia/lymphoma (T-LBL) using LSD1 transgenic mice. LSD1 expression is tightly regulated via alternative splicing and transcriptional repression in HSCs and is altered in most leukemias, especially T-LBL. Overexpression of the shortest isoform of LSD1, which is specifically repressed in quiescent HSCs and demethylates histone H3K9 more efficiently than other isoforms, increases self-renewal potential via upregulation of the HoxA family but retains multidifferentiation ability with a skewed differentiation to T-cell lineages at transcriptome levels in HSCs. Transgenic mice overexpressing LSD1 in HSCs did not show obvious abnormalities but developed T-LBL at very high frequency after γ-irradiation. LSD1 overexpression appears to be the first hit in T-cell leukemogenesis and provides an insight into novel strategies for early diagnosis and effective treatment of the disease.
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Taeko
authors.initials: T
authors.lastname: Wada
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Koyama
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Jiro
authors.initials: J
authors.lastname: Kikuchi
authors.affiliation: Department of Disease Model, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Honda
authors.affiliation: Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan; and.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Furukawa
mesh_terms: D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology; D044127:Epigenesis, Genetic; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D020033:Protein Isoforms; D056466:Histone Demethylases; C495195:KDM1A protein, human