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Somatic mutations of the CD95 gene in Hodgkin and Reed-Sternberg cells
M Müschen1, D Re, A Bräuninger
1Institute for Genetics, Department of Immunology, University of Cologne, Köln, Germany. markus.mueschen@uni-koeln.de
Insights
Somatic mutations in the CD95 gene may allow Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) to evade apoptosis. These CD95 gene mutations, along with IkappaB alpha gene mutations, contribute to cHD development.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- Classical Hodgkin's disease (cHD) involves Hodgkin and Reed-Sternberg (H/RS) cells, believed to originate from germinal center B cells.
- The mechanisms by which these precursor cells evade apoptosis, a critical process in germinal centers, remain largely unknown.
Purpose of the Study:
- To investigate somatic mutations in the CD95 gene within H/RS cells from cHD patients.
- To determine the role of CD95 gene mutations in the escape of H/RS cell precursors from apoptosis.
Main Methods:
- Single H/RS cells were isolated from 10 cHD cases using micromanipulation.
- The CD95 gene, including its 5' regions and the death domain-coding exon, was analyzed for somatic mutations.
- The IkappaB alpha gene was also examined for mutations.
Main Results:
- Clonal mutations within the CD95 gene were identified in H/RS cells from two cHD cases.
- Mutations included alterations in the 5' regions and the death domain, with some H/RS cells exhibiting monoallelic stop-codon or replacement mutations.
- These CD95 mutations are predicted to impair CD95 function, potentially hindering apoptosis.
- All analyzed H/RS cells also carried inactivating mutations in the IkappaB alpha gene.
Conclusions:
- Somatic mutations in the CD95 gene are present in a subset of cHD cases.
- These CD95 mutations may contribute to the survival of H/RS cell precursors by enabling escape from CD95-mediated apoptosis.
- Mutations in the IkappaB alpha gene appear to precede CD95 gene mutations in the oncogenic pathway of cHD.
Abstract:
Hodgkin and Reed-Sternberg (H/RS) cells in classical Hodgkin's disease (cHD) are thought to be derived from preapoptotic germinal center B cells. However, little is known about the transforming events rescuing the precursor of the H/RS cells from apoptosis. Given the importance of CD95 (Apo-1/Fas)-mediated apoptosis for negative selection within the germinal center, single micromanipulated H/RS cells from 10 cases of cHD were analyzed for somatic mutations within the CD95 gene. Three clonal mutations within the 5' regions were amplified from single H/RS cells in one case. From H/RS cells of another case, two mutations within the last exon coding for the death domain were detected. About half of these H/RS cells carried a monoallelic stop-codon; the remaining tumor cells harbored a monoallelic replacement mutation. Both mutations likely impair CD95 function. Because all these H/RS cells also bear clonal mutations inactivating the IkappaB alpha gene, the IkappaB alpha mutations occurred earlier than those of the CD95 gene in the sequence of transforming events leading to cHD. In conclusion, somatic mutations of the CD95 gene occur in a fraction of cHD cases and may favor the escape of the precursor of the H/RS clone from apoptosis.