title: The kelch protein KLHDC8B guards against mitotic errors, centrosomal amplification, and chromosomal instability.
abstract: The malignant cell in classical Hodgkin lymphoma (HL) is the binucleated giant Reed-Sternberg cell. Chromosomal instability and mitotic errors may contribute to HL pathogenesis; one potential mitotic regulator is the kelch protein KLHDC8B, which localizes to the midbody, is expressed during mitosis, and is mutated in a subset of familial and sporadic HL. We report that disrupting KLHDC8B function in HeLa cells, B lymphoblasts, and fibroblasts leads to significant increases in multinucleation, multipolar mitoses, failed abscission, asymmetric segregation of daughter nuclei, formation of anucleated daughter cells, centrosomal amplification, and aneuploidy. We recapitulated the major pathologic features of the Reed-Sternberg cell and concluded that KLHDC8B is essential for mitotic integrity and maintenance of chromosomal stability. The significant impact of KLHDC8B implicates the central roles of mitotic regulation and chromosomal segregation in the pathogenesis of HL and provides a novel molecular mechanism for chromosomal instability in HL.
authors.affiliation: Department of Pathology and the Institute for Stem Cell and Regenerative Medicine, University of Washington School of Medicine, Seattle, Washington 98109, USA. mkrem@u.washington.edu
authors.forename: Maxwell M
authors.initials: MM
authors.lastname: Krem
authors.forename: Ping
authors.initials: P
authors.lastname: Luo
authors.forename: Brandon I
authors.initials: BI
authors.lastname: Ing
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
mesh_terms: D000782:Aneuploidy; D001402:B-Lymphocytes / Q000166:cytology; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000502:physiology*; D002467:Cell Nucleus / Q000378:metabolism; D018385:Centrosome / Q000648:ultrastructure*; D043171:Chromosomal Instability; D048749:Cytokinesis; D005347:Fibroblasts / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006367:HeLa Cells; D006689:Hodgkin Disease / Q000378:metabolism; D006801:Humans; D007621:Karyotyping; D008938:Mitosis; D010641:Phenotype; D016539:Reed-Sternberg Cells / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C549813:KLHDC8B protein, human; D049452:Green Fluorescent Proteins