title: Role of casein kinase 1A1 in the biology and targeted therapy of del(5q) MDS.
abstract: The casein kinase 1A1 gene (CSNK1A1) is a putative tumor suppressor gene located in the common deleted region for del(5q) myelodysplastic syndrome (MDS). We generated a murine model with conditional inactivation of Csnk1a1 and found that Csnk1a1 haploinsufficiency induces hematopoietic stem cell expansion and a competitive repopulation advantage, whereas homozygous deletion induces hematopoietic stem cell failure. Based on this finding, we found that heterozygous inactivation of Csnk1a1 sensitizes cells to a CSNK1 inhibitor relative to cells with two intact alleles. In addition, we identified recurrent somatic mutations in CSNK1A1 on the nondeleted allele of patients with del(5q) MDS. These studies demonstrate that CSNK1A1 plays a central role in the biology of del(5q) MDS and is a promising therapeutic target.
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Rebekka K
authors.initials: RK
authors.lastname: Schneider
authors.affiliation: Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain; Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, GRETNHE, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain; Departament de Biologia Cellular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autonoma de Barcelona, 08193 Barcelona, Spain.
authors.forename: Vera
authors.initials: V
authors.lastname: Ademà
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Dirk
authors.initials: D
authors.lastname: Heckl
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marcus
authors.initials: M
authors.lastname: Järås
authors.affiliation: Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain; Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, GRETNHE, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Mallo
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Allegra M
authors.initials: AM
authors.lastname: Lord
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lisa P
authors.initials: LP
authors.lastname: Chu
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marie E
authors.initials: ME
authors.lastname: McConkey
authors.affiliation: Renal Division, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Kramann
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ann
authors.initials: A
authors.lastname: Mullally
authors.affiliation: Division of Hematology and Oncology, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093-0820, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bejar
authors.affiliation: Josep Carreras Leukaemia Research Institute (IJC), ICO-Hospital Germans Trias i Pujol, Universitat Autònoma de Barcelona (UAB), 08916 Badalona, Spain; Laboratori de Citogenètica Molecular, Servei de Patologia, Hospital del Mar, GRETNHE, IMIM (Hospital del Mar Research Institute), 08003 Barcelona, Spain.
authors.forename: Francesc
authors.initials: F
authors.lastname: Solé
authors.affiliation: Division of Hematology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of Harvard University and Massachusetts Institute of Technology, Cambridge, MA 02142, USA. Electronic address: bebert@partners.org.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Ebert
mesh_terms: D000368:Aged; D000818:Animals; D001483:Base Sequence; D047389:Casein Kinase I / Q000235:genetics / Q000378:metabolism*; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D057895:Haploinsufficiency; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D009190:Myelodysplastic Syndromes / Q000235:genetics*; D016133:Polymerase Chain Reaction; D055815:Young Adult
chemical_list: D017931:DNA Primers; D047389:Casein Kinase I