title: Aberrant overexpression of CD14 on granulocytes sensitizes the innate immune response in mDia1 heterozygous del(5q) MDS.
abstract: The myelodysplastic syndromes (MDSs) include a spectrum of stem cell malignancies characterized by an increased risk of developing acute myeloid leukemia. Heterozygous loss of chromosome 5q (del[5q]) is the most common cytogenetic abnormality in MDS. DIAPH1 is localized to 5q31 and encodes one of the formin proteins, mDia1, which is involved in linear actin polymerization. Mice with mDia1 deficiency develop hematologic features with age mimicking human myeloid neoplasm, but its role in the pathogenesis of MDS is unclear. Here we report that mDia1 heterozygous and knockout mice develop MDS phenotypes with age. In these mice, CD14 was aberrantly overexpressed on granulocytes in a cell-autonomous manner, leading to a hypersensitive innate immune response to lipopolysaccharide (LPS) stimuli through CD14/Toll-like receptor 4 signaling. Chronic stimulation with LPS accelerated the development of MDS in mDia1 heterozygous and knockout mice that can be rescued by lenalidomide. Similar findings of CD14 overexpression were observed on the bone marrow granulocytes of del(5q) MDS patients. Mechanistically, mDia1 deficiency led to a downregulation of membrane-associated genes and a specific upregulation of CD14 messenger RNA in granulocytes, but not in other lineages. These results underscore the significance of mDia1 heterozygosity in deregulated innate immune responses in del(5q) MDS.
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
authors.forename: Ganesan
authors.initials: G
authors.lastname: Keerthivasan
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
authors.forename: Yang
authors.initials: Y
authors.lastname: Mei
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
authors.forename: Baobing
authors.initials: B
authors.lastname: Zhao
authors.affiliation: Department of Hematopathology and Laboratory Medicine and Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA;
authors.forename: Chad E
authors.initials: CE
authors.lastname: Harris
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
authors.forename: Juehua
authors.initials: J
authors.lastname: Gao
authors.affiliation: Department of Hematopathology and Laboratory Medicine and Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
authors.forename: Ashley A
authors.initials: AA
authors.lastname: Basiorka
authors.affiliation: Center for Genetic Medicine, Northwestern University, Chicago, IL;
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Schipma
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
authors.forename: James
authors.initials: J
authors.lastname: McElherne
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY; and.
authors.forename: Amit K
authors.initials: AK
authors.lastname: Verma
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pellagatti
authors.affiliation: Nuffield Division of Clinical Laboratory Sciences, John Radcliffe Hospital, Oxford, United Kingdom.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Boultwood
authors.affiliation: Department of Hematopathology and Laboratory Medicine and Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
authors.forename: Alan F
authors.initials: AF
authors.lastname: List
authors.affiliation: Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA;
authors.forename: David A
authors.initials: DA
authors.lastname: Williams
authors.affiliation: Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, IL;
authors.forename: Peng
authors.initials: P
authors.lastname: Ji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D005260:Female; D000080865:Formins; D005786:Gene Expression Regulation; D006098:Granulocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D006579:Heterozygote; D006801:Humans; D007113:Immunity, Innate; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C108962:DIAPH1 protein, human; C491464:Diap1 protein, mouse; D000080865:Formins; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D012333:RNA, Messenger; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4