title: Mutations in CHD2 cause defective association with active chromatin in chronic lymphocytic leukemia.
abstract: Great progress has recently been achieved in the understanding of the genomic alterations driving chronic lymphocytic leukemia (CLL). Nevertheless, the specific molecular mechanisms governing chromatin remodeling in CLL are unknown. Here we report the genetic and functional characterization of somatic mutations affecting the chromatin remodeler CHD2, one of the most frequently mutated genes in CLL (5.3%) and in monoclonal B lymphocytosis (MBL, 7%), a B-cell expansion that can evolve to CLL. Most of the mutations affecting CHD2, identified by whole-exome sequencing of 456 CLL and 43 MBL patients, are either truncating or affect conserved residues in functional domains, thus supporting a putative role for CHD2 as a tumor suppressor gene. CHD2 mutants show altered nuclear distribution, and a chromodomain helicase DNA binding protein 2 (CHD2) mutant affected in its DNA-binding domain exhibits defective association with active chromatin. Clinicobiological analyses show that most CLL patients carrying CHD2 mutations also present mutated immunoglobulin heavy chain variable region genes (IGHVs), being the most frequently mutated gene in this prognostic subgroup. This is the first study providing functional evidence supporting CHD2 as a cancer driver and opens the way to further studies of the role of this chromatin remodeler in CLL.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain;
authors.forename: David
authors.initials: D
authors.lastname: Rodríguez
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain;
authors.forename: Gabriel
authors.initials: G
authors.lastname: Bretones
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain;
authors.forename: Víctor
authors.initials: V
authors.lastname: Quesada
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica and Servicio de Hematología, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Neus
authors.initials: N
authors.lastname: Villamor
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain;
authors.forename: Javier R
authors.initials: JR
authors.lastname: Arango
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica and Servicio de Hematología, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Armando
authors.initials: A
authors.lastname: López-Guillermo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain;
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Ramsay
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica and Servicio de Hematología, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Tycho
authors.initials: T
authors.lastname: Baumann
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain;
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Quirós
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica and Servicio de Hematología, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Alba
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica and Servicio de Hematología, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: Cristina
authors.initials: C
authors.lastname: Royo
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica and Servicio de Hematología, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and.
authors.forename: José I
authors.initials: JI
authors.lastname: Martín-Subero
authors.affiliation: Unidad de Hematopatología, Servicio de Anatomía Patológica and Servicio de Hematología, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and Universitat de Barcelona, Barcelona, Spain.
authors.forename: Elías
authors.initials: E
authors.lastname: Campo
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain;
authors.forename: Carlos
authors.initials: C
authors.lastname: López-Otín
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D009154:Mutation; D017386:Sequence Homology, Amino Acid
chemical_list: C575189:CHD2 protein, human; D002843:Chromatin; D004268:DNA-Binding Proteins