title: Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells.
abstract: Classical Hodgkin lymphoma (cHL) is a malignancy of B-cell origin in which the neoplastic cells, known as "Reed-Sternberg" (RS) cells, are characteristically binucleated. Here we describe a family where multiple individuals developing cHL have inherited a reciprocal translocation between chromosomes 2 and 3. The translocation disrupts KLHDC8B, an uncharacterized gene from a region (3p21.31) previously implicated in lymphoma and related malignancies, resulting in its loss of expression. We tested KLHDC8B as a candidate gene for cHL and found that a 5'-UTR polymorphism responsible for decreasing its translational expression is associated with cHL in probands from other families with cHL and segregates with disease in those pedigrees. In one of three informative sporadic cases of cHL, we detected loss of heterozygosity (LOH) for KLHDC8B in RS cells, but not reactive T lymphocytes, purified from a malignant lymph node. KLHDC8B encodes a protein predicted to contain seven kelch repeat domains. KLHDC8B is expressed during mitosis, where it localizes to the midbody structure connecting cells about to separate during cytokinesis, and it is degraded after cell division. Depletion of KLHDC8B through RNA interference leads to an increase in binucleated cells, implicating its reduced expression in the formation of cHL's signature RS cell.
authors.affiliation: Department of Genome Sciences, University of Washington School of Medicine, Seattle, WA 98195, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Salipante
authors.forename: Matthew E
authors.initials: ME
authors.lastname: Mealiffe
authors.forename: Jeremy
authors.initials: J
authors.lastname: Wechsler
authors.forename: Maxwell M
authors.initials: MM
authors.lastname: Krem
authors.forename: Yajuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Shinae
authors.initials: S
authors.lastname: Namkoong
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Tomas
authors.initials: T
authors.lastname: Kirchhoff
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
authors.forename: Henry
authors.initials: H
authors.lastname: Lynch
authors.forename: Peter H
authors.initials: PH
authors.lastname: Wiernik
authors.forename: Mikhail
authors.initials: M
authors.lastname: Roshal
authors.forename: Mary Lou
authors.initials: ML
authors.lastname: McMaster
authors.forename: Margaret
authors.initials: M
authors.lastname: Tucker
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Fromm
authors.forename: Lynn R
authors.initials: LR
authors.lastname: Goldin
authors.forename: Marshall S
authors.initials: MS
authors.lastname: Horwitz
mesh_terms: D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D001483:Base Sequence; D002467:Cell Nucleus / Q000235:genetics*; D002889:Chromosomes, Human, Pair 2; D002893:Chromosomes, Human, Pair 3; D005260:Female; D020022:Genetic Predisposition to Disease; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D016539:Reed-Sternberg Cells / Q000378:metabolism; D016415:Sequence Alignment; D012689:Sequence Homology, Nucleic Acid; D055815:Young Adult
chemical_list: D020121:5' Untranslated Regions; D000951:Antigens, Neoplasm
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