Survival of the malignant Hodgkin and Reed/Sternberg (HRS) cells in classical 
Hodgkin lymphoma (cHL) is dependent on constitutive activation of the nuclear 
factor kappaB (NF-kappaB) transcription factor. The deubiquitinating enzyme CYLD 
is a negative regulator of NF-kappaB and known to function as a tumor 
suppressor. To determine whether CYLD mutations play a role in cHL pathogenesis, 
we sequenced the gene in cHL cell lines and microdissected HRS cells obtained 
from lymph-node biopsies. A biallelic inactivation by mutations was found in the 
cHL cell-line KM-H2. However, the other seven cHL cell lines analyzed and HRS 
cells of 10 primary cHL cases did not show any mutations. By interphase 
cytogenetics, a (sub)clonal biallelic CYLD deletion was observed by interphase 
cytogenetics in 1 of 29 primary cHL, whereas signal patterns indicating 
decreased CYLD copy numbers were observed in a total of 10 of 29 primary cases. 
Our results suggest that biallelic CYLD mutations are rarely involved in cHL 
pathogenesis. Nevertheless, it is remarkable that KM-H2 cells, besides the CYLD 
mutations, also carry inactivating mutations in the genes of two other NF-kappaB 
inhibitors, that is, NFKBIA and TNFAIP3, exemplifying that multiple lesions in 
regulators of this signaling pathway can likely cooperatively contribute to the 
strong NF-kappaB activity of these cells.