Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells Journal Article
| Authors: | Salipante, S. J.; Mealiffe, M. E.; Wechsler, J.; Krem, M. M.; Liu, Y.; Namkoong, S.; Bhagat, G.; Kirchhoff, T.; Offit, K.; Lynch, H.; Wiernik, P. H.; Roshal, M.; McMaster, M. L.; Tucker, M.; Fromm, J. R.; Goldin, L. R.; Horwitz, M. S. |
| Article 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. |
| Keywords: | adolescent; adult; controlled study; aged; aged, 80 and over; middle aged; young adult; carrier protein; unclassified drug; gene mutation; gene translocation; human cell; mutation; t lymphocyte; animals; cell division; genetic predisposition to disease; gene expression; protein degradation; rna interference; chromosomes, human, pair 2; hodgkin disease; b lymphocyte; pedigree; gene mapping; antigens, neoplasm; sequence alignment; 5' untranslated region; base sequence; cell nucleus; heterozygosity loss; sequence homology, nucleic acid; chromosome 2; cytokinesis; dna polymorphism; protein klhdc8b; chromosome 3; classical hodgkin lymphoma; nuclear division; reciprocal chromosome translocation; reed sternberg cell; 5' untranslated regions; chromosomes, human, pair 3; reed-sternberg cells |
| Journal Title: | Proceedings of the National Academy of Sciences of the United States of America |
| Volume: | 106 |
| Issue: | 35 |
| ISSN: | 0027-8424 |
| Publisher: | National Academy of Sciences |
| Date Published: | 2009-09-01 |
| Start Page: | 14920 |
| End Page: | 14925 |
| Language: | English |
| DOI: | 10.1073/pnas.0904231106 |
| PUBMED: | 19706467 |
| PROVIDER: | scopus |
| PMCID: | PMC2736436 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 3" - "Export Date: 30 November 2010" - "CODEN: PNASA" - "Source: Scopus" |
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