title: RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity.
abstract: RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1(+/-) hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1(+/-) cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1(+/+) cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: D W L
authors.initials: DW
authors.lastname: Chin
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Sakurai
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: G S S
authors.initials: GS
authors.lastname: Nah
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: L
authors.initials: L
authors.lastname: Du
authors.affiliation: Institute of Molecular and Cell Biology, A*STAR, Singapore.
authors.forename: B
authors.initials: B
authors.lastname: Jacob
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|International Research Center for Medical Sciences, Kumamoto University, Kumamato, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: T
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|International Research Center for Medical Sciences, Kumamoto University, Kumamato, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Suda
authors.affiliation: Department of Paediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: G
authors.initials: G
authors.lastname: Huang
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: X-Y
authors.initials: XY
authors.lastname: Fu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Institute of Molecular and Cell Biology, A*STAR, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Nakajima
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|International Research Center for Medical Sciences, Kumamoto University, Kumamato, Japan.|Institute of Bioengineering and Nanotechnology, A*STAR, Singapore.|Department of Paediatrics, National University of Singapore, Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Osato
mesh_terms: D000818:Animals; D001791:Blood Platelet Disorders / Q000235:genetics; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics*; D016207:Cytokines / Q000494:pharmacology; D004195:Disease Models, Animal; D004351:Drug Resistance / Q000235:genetics*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D005838:Genotype; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D057895:Haploinsufficiency; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D016207:Cytokines; D018832:Molecular Chaperones; C484745:PIAS3 protein, human; D050828:Protein Inhibitors of Activated STAT; D019718:Receptors, CXCR4; D050796:STAT3 Transcription Factor; D016179:Granulocyte Colony-Stimulating Factor