Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells

Stephen J. Salipante, Matthew E. Mealiffe, Jeremy Wechsler, Maxwell M. Krem, Yajuan Liu, Shinae Namkoong, Govind Bhagat, Tomas Kirchhoff, Kenneth Offit, Henry T. Lynch, Peter H. Wiernik, Mikhail Roshal, Mary Lou McMaster, Margaret Tucker, Jonathan R. Fromm, Lynn R. Goldin, Marshall S. Horwitz

Research output: Contribution to journalArticle

35 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)14920-14925
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number35
DOIs
StatePublished - Sep 1 2009

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Hodgkin Disease
Reed-Sternberg Cells
Mutation
Genes
Proteins
Chromosomes, Human, Pair 3
Chromosomes, Human, Pair 2
Cytokinesis
Loss of Heterozygosity
5' Untranslated Regions
Pedigree
RNA Interference
Mitosis
Cell Division
Lymphoma
Neoplasms
B-Lymphocytes
Lymph Nodes
T-Lymphocytes

All Science Journal Classification (ASJC) codes

  • General

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Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells. / Salipante, Stephen J.; Mealiffe, Matthew E.; Wechsler, Jeremy; Krem, Maxwell M.; Liu, Yajuan; Namkoong, Shinae; Bhagat, Govind; Kirchhoff, Tomas; Offit, Kenneth; Lynch, Henry T.; Wiernik, Peter H.; Roshal, Mikhail; McMaster, Mary Lou; Tucker, Margaret; Fromm, Jonathan R.; Goldin, Lynn R.; Horwitz, Marshall S.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 35, 01.09.2009, p. 14920-14925.

Research output: Contribution to journalArticle

Salipante, SJ, Mealiffe, ME, Wechsler, J, Krem, MM, Liu, Y, Namkoong, S, Bhagat, G, Kirchhoff, T, Offit, K, Lynch, HT, Wiernik, PH, Roshal, M, McMaster, ML, Tucker, M, Fromm, JR, Goldin, LR & Horwitz, MS 2009, 'Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 35, pp. 14920-14925. https://doi.org/10.1073/pnas.0904231106
Salipante, Stephen J. ; Mealiffe, Matthew E. ; Wechsler, Jeremy ; Krem, Maxwell M. ; Liu, Yajuan ; Namkoong, Shinae ; Bhagat, Govind ; Kirchhoff, Tomas ; Offit, Kenneth ; Lynch, Henry T. ; Wiernik, Peter H. ; Roshal, Mikhail ; McMaster, Mary Lou ; Tucker, Margaret ; Fromm, Jonathan R. ; Goldin, Lynn R. ; Horwitz, Marshall S. / Mutations in a gene encoding a midbody kelch protein in familial and sporadic classical Hodgkin lymphoma lead to binucleated cells. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 35. pp. 14920-14925.
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AU - Mealiffe, Matthew E.

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AU - Krem, Maxwell M.

AU - Liu, Yajuan

AU - Namkoong, Shinae

AU - Bhagat, Govind

AU - Kirchhoff, Tomas

AU - Offit, Kenneth

AU - Lynch, Henry T.

AU - Wiernik, Peter H.

AU - Roshal, Mikhail

AU - McMaster, Mary Lou

AU - Tucker, Margaret

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