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Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2009 Sep 01; Vol. 106 (35), pp. 14920-5. Date of Electronic Publication: 2009 Aug 12. - Publication Year :
- 2009
-
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.
- Subjects :
- 5' Untranslated Regions
Adolescent
Adult
Aged
Aged, 80 and over
Animals
Base Sequence
Female
Genetic Predisposition to Disease
Hodgkin Disease pathology
Humans
Male
Middle Aged
Pedigree
Reed-Sternberg Cells metabolism
Sequence Alignment
Sequence Homology, Nucleic Acid
Young Adult
Antigens, Neoplasm genetics
Cell Nucleus genetics
Chromosomes, Human, Pair 2
Chromosomes, Human, Pair 3
Hodgkin Disease genetics
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 106
- Issue :
- 35
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 19706467
- Full Text :
- https://doi.org/10.1073/pnas.0904231106