Cancer Research Cell Death Mechanisms and Cancer Therapy Jordan
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Müschen, M.
Right arrow Articles by Rajewsky, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Müschen, M.
Right arrow Articles by Rajewsky, K.
[Cancer Research 60, 5640-5643, October 15, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Somatic Mutations of the CD95 Gene in Hodgkin and Reed-Sternberg Cells1

Markus Müschen2, Daniel Re, Andreas Bräuninger, Jürgen Wolf, Martin-Leo Hansmann, Volker Diehl, Ralf Küppers and Klaus Rajewsky

Institute for Genetics, Department of Immunology [M. M., R. K., K. R.], and the Department for Internal Medicine I [M. M., D. R., J. W., V. D., R. K.], University of Cologne, 50931 Köln, and Department of Pathology [A. B., M-L. H.], University of Frankfurt, 60596 Frankfurt, Germany


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
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 I{kappa}B{alpha} gene, the I{kappa}B{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.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
H/RS3 cells have recently been demonstrated to be derived from GC B cells (1) . In many cases of classical cHD, the H/RS cells have lost their capacity to express a functional B-cell receptor due to destructive somatic mutations of the rearranged immunoglobulin genes (2, 3, 4) . As GC B cells are destined to die by apoptosis within the GC unless they are positively selected for expression of a B-cell receptor with high affinity to antigen (5) , the hypothesis was developed that cHD may represent the outgrowth of a preapoptotic GC B cell (1, 2, 3, 4) . It remains an open question, however, how the precursor of the H/RS cell clone escaped apoptosis during the GC reaction.

In the B lineage, CD95 (Apo-1/Fas) is expressed specifically at the GC stage of differentiation (6) . CD95-mediated apoptosis was proposed to represent an important mechanism for negative selection of B cells within the GC (6 , 7) . Deleterious mutations of the CD95 gene should therefore confer resistance of GC B cells to a major pathway of apoptosis in the GC. Indeed, in CD95-deficient lpr mice, autoreactive B cells can escape negative selection (8) , resulting in lymphadenopathy, enlargement of liver and spleen, and propensity to autoimmunity (8) and B-cell lymphoma (9) . Germ-line mutations of the CD95 gene leading to autoimmune lymphoproliferative syndrome and predisposing to B-cell lymphoma and other malignancies occur in humans as well (10 , 11) . Notably, some patients carrying deleterious mutations of the CD95 gene in their germ-line developed lymphocyte- predominant HD (12) or cHD (11) . Somatic mutations impairing the transduction of the apoptosis signal were observed in a number of lymphoid malignancies (13, 14, 15) . In lymphomas derived from antigen-experienced B cells, mutations of the CD95 gene may have been acquired during the GC reaction and represent a side effect of somatic hypermutation acting outside the immunoglobulin loci.4 However, T cell-derived malignancies (15) and solid tumors (16, 17, 18) also were found to harbor somatic mutations of the CD95 gene. Deleterious mutations of exon 9, coding for the DD, act in a dominant negative way impairing CD95 function as a whole (10) . The dominant negative effect of monoallelic mutations within the DD is likely attributable to the trimerization of the CD95 receptor on the cell surface. The DD is a highly conserved region that is required and sufficient for the transduction of the death signal (19) . Given the functional importance of this region, it is not surprising that about 60% of somatic mutations in lymphoid or solid tumors involve this region (18) .

It was recently shown that several HD-derived cell lines, although expressing CD95, are resistant to CD95-mediated apoptosis (20) . To clarify whether impairment of CD95-mediated apoptosis is due to somatic mutations of the CD95 gene, which may thus contribute to the persistence of the preapoptotic GC B cells developing toward cHD, single micromanipulated H/RS cells from 10 cases of cHD were analyzed for such mutations.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Case Description.
Information on the 10 cases of cHD from which single micromanipulated H/RS cells were analyzed is given in Table 1Citation . Cases I–III, IV–VIII, and X have been studied previously (Refs. 4 , 21 , and 3 , respectively).


View this table:
[in this window]
[in a new window]

  		Table 1 Case description of patients with cHD

 
Immunostaining.
For immunostaining, 7-µm-thick frozen tissue sections were stained using antibodies against CD30, CD20, anaplastic lymphoma kinase-1 (Dako), CD15 (Becton Dickinson, Mountain View, CA), and CD3 (Ortho Diagnostic Systems, Raritan, NJ).

Micromanipulation and Single-Cell PCR for the CD95 Gene.
Stained cells were mobilized and aspirated with the help of a micropipette fixed to a hydraulic micromanipulator. Buffer covering the sections was aspirated as negative controls for PCR analysis.

For all micromanipulated H/RS cells, a whole genome preamplification step (22) was performed. The H/RS cells were first analyzed for immunoglobulin-heavy chain and immunoglobulin {kappa} and {lambda}-light chain as well as TCRß gene rearrangements. In nine cases, the CD95 gene was amplified only from preamplification reactions that already gave rise to the H/RS cell-specific immunoglobulin or to TCRß gene rearrangements. In one case (case V; Table 2Citation ), no preamplification reactions were available, and H/RS cells were subjected directly to two rounds of PCR amplification of the CD95 gene. Aliquots of 4 µl from these reactions were then subjected to two rounds of seminested PCR amplification as described previously. Briefly, rearranged VH-, V{kappa}-, and V{lambda}-genes were amplified using family-specific framework region I V-gene primers and two sets of JH-, J{kappa}- and J{lambda}-primers in a seminested approach (3) . TCRß VDJ, and TCRß DJ gene rearrangements were amplified as described previously (4) . PCR products were gel-purified and directly sequenced using the BigDye Terminator cycle sequencing kit and an automated sequencer (ABI 377; Applied Biosystems, Germany). As depicted in Fig. 1Citation , two regions of the CD95 gene were analyzed by single-cell PCR. Exon IX coding for the DD (Fig. 1)Citation was amplified from H/RS cells of all 10 cases of cHD using 5'-CAC TAA TGG GAA TTT CAT TTA GA-3' as external forward, 5'-TGG GAA TTT CAT TTA GAA AAA CA-3' as internal forward, 5'-TAA TTG CAT ATA CTC AGA ACT GA-3' as external reverse, and 5'-TAC TCA GAA CTG AAT TTG TTG T-3' as internal reverse primers in a nested PCR. For cases I, II, III, IX, and X, a fragment encompassing the 5' untranslated and coding regions of exon I and the 5' part of the first intron (Fig. 1)Citation was amplified from multiple H/RS cells using 5'-ACC ACCGGG GCT TTT CGT GA-3' as external forward, 5'-TGA GCT CGT CTC TGA TCT CG-3' as internal forward, 5'-TAT CTG TTC TGA AGG CTG CAG-3' as external reverse, and 5'-CGG AGC GGA CCT TTG GCT-3' as internal reverse primers.


View this table:
[in this window]
[in a new window]

  		Table 2 Sequence analysis of 5' regions and the DD of the CD95 gene amplified from single micromanipulated H/RS cells

 


View larger version (8K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 1. Organization of the CD95 gene and PCR strategy. The organization of the CD95 gene (comprising exons I to IX) is depicted (not to scale). From H/RS cells of five primary cases of cHD a 750 bp fragment encompassing 5' untranslated (5'UTR, gray boxes) and coding (black boxes) regions of the first exon and a p53 responsive intronic enhancer was amplified. From H/RS cells of ten primary cases of cHD a 440 bp fragment containing the region of exon IX coding for the death domain of CD95 was amplified. Mismatches to known germ-line sequences are depicted by vertical lines (five somatic mutations with arrowheads, two novel germ-line polymorphisms without).

 
Determination of EBV Infection.
EBV infection of H/RS cells was examined by in situ hybridization for noncoding EBV-encoded small RNAs, by amplification of a fragment of the EBV nuclear antigen-1 gene from single micromanipulated H/RS cells (4) , or by immunostaining for latent membrane protein 1.


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
Single H/RS cells from 10 cases of cHD (Table 1)Citation were micromanipulated and subjected to whole genome preamplification. With one exception, for further analysis only whole genome preamplification reactions of H/RS cells were selected from which the immunoglobulin or TCRß gene rearrangement defining the H/RS tumor clone could be amplified (Table 2Citation ; see "Materials and Methods"). The last exon of the CD95 gene coding for the DD was amplified from multiple H/RS cells of all 10 cases. From H/RS cells of five cases, a 750-bp fragment of the CD95 gene encompassing 5'untranslated and coding regions of exon I and a p53-responsive enhancer within the first intron was analyzed, here collectively termed 5'R (Fig. 1Citation ; Table 2Citation ).

In one of 10 cases of cHD, the H/RS cells harbored monoallelic somatic mutations of the last exon. From all 12 H/RS cells analyzed from that case, a somatically mutated CD95 gene was coamplified with a wt allele (Fig. 2A)Citation . Unexpectedly, the mutations are not shared between all H/RS cells; five of the cells carry a mutation leading to an amino acid replacement at codon 282 (Ile->Val). From seven H/RS cells of the same case, a mutation that truncates the DD through a translational stop at codon 295 was amplified. Given that all truncating or replacement mutations within the highly conserved DD described thus far act in a dominant negative way and are related to a clinical phenotype (10 , 11 , 18) , these two mutations are also likely to interfere with CD95-mediated apoptosis.



View larger version (34K):
[in this window]
[in a new window]
[Download PPT slide]
  		Fig. 2. Distinct mutations of the CD95 gene define two subclones of the H/RS cells in case IV. A, three sequence variants obtained from 12 micromanipulated H/RS cells and whole tissue DNA (as a control for germ-line polymorphisms) are shown (R, A and G; K, G and T). B, based on the presence of clonal immunoglobulin gene rearrangements and clonal mutations of the I{kappa}B{alpha} gene together with two distinct mutations of the CD95 gene defining two subclones the scenario of a possible sequence of transforming events leading to cHD is depicted.

 
These mutations either define two distinct subclones (Fig. 2)Citation or indicate the presence of a third allele of the CD95 gene in the H/RS cells. The latter possibility, however, is unlikely, as both mutations were not concomitantly amplified from any of the H/RS cells; whereas PCR amplification from all 12 H/RS cells gave rise to one of the mutant alleles together with a wt allele. The two H/RS cell populations defined by distinct mutations of the CD95 gene belong to the same clone, as they harbored both the same immunoglobulin gene rearrangements (Table 2Citation , Fig. 2ACitation ) and biallelic clonal mutations of the I{kappa}B{alpha} gene (21) .

The 5'R of the CD95 gene from H/RS cells of five cases of cHD also were amplified and sequenced. Within these regions, two novel intronic germ-line polymorphisms of the CD95 gene were identified (Fig. 1Citation , Table 2Citation )4 and confirmed by sequencing from whole-tissue DNA or single micromanipulated CD3+ T cells from tissue sections of the same case. Using the two polymorphisms as allelic markers, none of four informative cases showed allelic loss of the CD95 gene (i.e., each polymorphic allele could be amplified at least once). From the H/RS cells of one case, three clonal mutations within the 5'R were amplified. The three mutations in this case were found either concomitantly (four cells) or only the wt allele was amplified (two cells; Table 2Citation ), indicating that the three mutations are present on one allele. These three mutations are unlikely to silence CD95 function, as only noncoding regions were involved. A p53-responsive intronic enhancer that is required for CD95 transcription (23) is also situated in this region but was not mutated.

Extending a previous analysis on mutations of the CD95 gene in cHD-derived cell lines (20) , the DD and 5'R were analyzed in the putative cHD cell lines L1236, L428, L540, L591, DEV, HDLM-2, and KM-H2, and no mutation was found.


   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
As opposed to the malignant cells of other lymphomas, H/RS cells are thought to be derived from a preapoptotic GC B cell. Therefore, defects in the transduction of proapoptotic signals or in the execution of the apoptosis program may be particularly important for the development of cHD. In about 50% of cases of cHD, EBV infection of the H/RS cells and expression of the EBV-encoded latent membrane proteins 1 and -2a may play a role in the rescue of the H/RS cell precursors from apoptosis (reviewed in Ref. 1 ). In a search for genetic defects in H/RS cells, p53 mutations (24) and bcl-2 translocations (25) were investigated in cHD at the single-cell level; however, no such events were found. Recently, deleterious mutations of the I{kappa}B{alpha} gene leading to constitutive nuclear NF-{kappa}B activity in H/RS cells were identified as the first genetic defect that may counteract the physiological susceptibility of the tumor precursor to apoptosis (21) . However, I{kappa}B{alpha} inactivation due to deleterious somatic mutations was detected only in one of five primary cases and two of eight cHD-derived cell lines, indicating that other factors most likely contribute to apoptosis-resistance of H/RS cells.

As H/RS cells have been shown to coexpress CD95 with its apoptosis-inducing ligand (26) , defects in CD95 signaling may be critical for the survival of the tumor cells. Therefore, we studied 10 primary cases of cHD for CD95 mutations. In 2 of the 10 cases, somatic mutations in the CD95 gene were detected, one of which is likely to lack CD95 function as a result of destructive mutations. In the other case, three mutations were detected in the noncodoing 5'R whose impact on CD95 function remains unclear.

For all 10 cases multiple H/RS cells were analyzed; thus most likely for all cases both CD95 alleles were amplified. For the five cases that were informative for at least one polymorphic marker or which harbored somatic mutations, the presence of both alleles could indeed be verified. Thus, allelic loss of the CD95 gene appears to occur rarely, if at all, in cHD. On the basis of the assumption of biallelic amplification of exon IX (440 bp) for 10 cases and 5'R (750 bp) for 5 cases, a rough estimate would yield a mutation frequency of 3.1 x 10-4/bp for the CD95 gene in H/RS cells. This frequency is not significantly different from that seen in normal GC B cells (2.2 x 10-4/bp).4 Therefore, the somatic mutations within the CD95 gene in H/RS cells could merely reflect their GC B-cell nature. This particularly applies to somatic mutations within the 5'R, because about 15% of normal GC B cells carry CD95 mutations in this region, which likely arise as a byproduct of the somatic hypermutation process.4

Somatic mutations within the DD frequently interfere with apoptosis-signaling, act in a dominant negative manner, and have been repeatedly observed in malignancy. Therefore, the two DD mutations amplified from H/RS cells in this study could well be involved in the malignant progression toward cHD. The H/RS cell population in the patient in question shares clonal somatically mutated immunoglobulin gene rearrangements and clonal mutations of the I{kappa}B{alpha} gene but is diversified by distinct mutations within the DD. The presence of clonal mutations of the I{kappa}B{alpha} gene together with two "subclonal" mutations within the DD of the CD95 gene suggests that I{kappa}B{alpha} inactivation occurred earlier than the loss of CD95 function in the sequence of transforming events leading to cHD (Fig. 2B)Citation . The finding that among a population of H/RS cells with clonal I{kappa}B{alpha} mutations two daughter cells with distinct CD95 mutations established the H/RS tumor clone strongly suggests that the cells harboring these mutations were indeed positively selected and had a survival advantage. The consecutive silencing of I{kappa}B{alpha} and CD95 in this case is reminiscent of the model by Fearon and Vogelstein (27) , who identified a recurrent pattern of multistep carcinogenesis toward colorectal cancer. For future studies it will be interesting to clarify whether a recurrent sequence of transforming events can also be identified in cHD.

Taken together, somatic mutations in the DD of the CD95 gene occur in a fraction of cases of cHD and may contribute to the pathogenesis of the lymphoma by impairing CD95-mediated apoptosis of the tumor cells.


   ACKNOWLEDGMENTS
 
We thank Nadia Massoudi and Julia Jesdinsky for excellent technical assistance, Verena Distler for helping with preamplification reactions, and Berit Jungnickel, Tina Goossens, and Julia Kurth for critical discussions.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 This work was supported by the Deutsche Forschungsgemeinschaft through SFB 502, the Deutsche Krebshilfe (Dr. Mildred Scheel Stiftung), and the Land Nordrhein-Westfalen. D. R. is supported by the Friedrich und Marie Sophie Moritz’sche Stiftung (Cologne, Germany). R. K. is supported by the Heisenberg program of the Deutsche Forschungsgemeinschaft. M. M. is holding a postdoctoral fellowship from the Cancer Research Institute (New York, NY; Tumor Immunology Program). Back

2 To whom requests for reprints should be addressed, at Universität zu Köln, Institute for Genetics, Department of Immunology, LFI E4 R705, Joseph-Stelzmann-Straße 9, 50931 Köln, Germany. Fax: 49-221-4786383; E-mail: markus.mueschen{at}uni-koeln.de Back

3 The abbreviations used are: H/RS, Hodgkin and Reed-Sternberg; cHD, classical Hodgkin’s disease; HD, Hodgkin’s disease; DD, death domain; GC, germinal center; 5'R, 5' region; wt, wild type; TCR, T-cell receptor. Back

4 M. Müschen et al., submitted for publication. Back

Received 6/26/00. Accepted 8/22/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

  1. Küppers R., Rajewsky K. The origin of Hodgkin and Reed-Sternberg cells in Hodgkin’s disease. Annu. Rev. Immunol., 16: 471-490, 1998.[Medline]
  2. Küppers R., Rajewsky K., Zhao M., Simons G., Laumann R., Fischer R., Hansmann M. L. Hodgkin disease: Hodgkin and Reed-Sternberg cells picked from histological sections show clonal immunoglobulin gene rearrangements and appear to be derived from B cells at various stages of development. Proc. Natl. Acad. Sci. USA, 91: 10962-10967, 1994.[Abstract/Free Full Text]
  3. Kanzler H., Küppers R., Hansmann M. L., Rajewsky K. Hodgkin and Reed-Sternberg cells in Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from (crippled) germinal center B cells. J. Exp. Med., 184: 1495-1503, 1996.[Abstract/Free Full Text]
  4. Müschen M., Rajewsky K., Bräuninger A., Baur A. S., Oudejans J. J., Roers A., Hansmann M. L., Küppers R. Rare occurrence of classical Hodgkin’s disease as a T cell lymphoma. J. Exp. Med., 191: 387-394, 2000.[Abstract/Free Full Text]
  5. Rajewsky K. Clonal selection and learning in the antibody system. Nature (Lond.), 381: 751-758, 1996.[Medline]
  6. Martinez-Valdez H., Guret C., de Bouteiller O., Fugier I., Banchereau J., Liu Y. J. Human germinal center B cells express the apoptosis-inducing genes Fas, c-myc, p53 and Bax but not the survival gene bcl-2. J. Exp. Med., 183: 971-977, 1996.[Abstract/Free Full Text]
  7. Liu Y. J., de Bouteiller O., Fugier-Vivier I. Mechanisms of selection and differentiation in germinal centers. Curr. Opin. Immunol., 9: 256-262, 1997.[Medline]
  8. Watanabe-Fukunaga R., Brannan P. E., Copeland N. G., Jenkins N., Nagata S. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature (Lond.), 356: 314-317, 1992.[Medline]
  9. Davidson W. F., Giese T., Fredrickson T. N. Spontaneous development of plasmacytoid tumors in mice with defective Fas-Fas ligand interactions. J. Exp. Med., 187: 1825-1838, 1998.[Abstract/Free Full Text]
  10. Fisher G. H., Rosenberg F. J., Straus S. E., Dale J. K., Middleton L. A., Lin A. Y., Strober W., Lenardo M. J. Dominant interfering Fas gene mutations impair apoptosis in a human autoimmune lymphoproliferative syndrome. Cell, 81: 935-946, 1995.[Medline]
  11. Peters A. M., Kohfink B., Martin H., Griesinger F., Wörmann B., Gahr M., Roesler J. Defective apoptosis due to a point mutation in the death domain of CD95 associated with autoimmune lymphoproliferative syndrome, T-cell lymphoma, and Hodgkin’s disease. Exp. Hematol., 27: 868-874, 1999.[Medline]
  12. Lim M. S., Straus S. E., Dale J. K., Fleischer T. A., Stetler-Stevenson M., Strober W., Sneller M. C., Puck J. M., Lenardo M. J., Elenitoba-Johnson K. S., Lin A. Y., Raffeld M., Jaffé E. S. Pathological findings in human autoimmune lymphoproliferative syndrome. Am. J. Pathol., 153: 1541-1550, 1998.[Abstract/Free Full Text]
  13. Landowski T. H., Qu N., Buyuksal I., Painter J. S., Dalton W. S. Mutations in the Fas antigen in patients with multiple myeloma. Blood, 90: 4266-4270, 1997.[Abstract/Free Full Text]
  14. Grønbæk K., Straten P. T., Ralfkiæer E., Ahrenkiel V., Andersen M. K., Hansen N. E., Zeuthen J., Hou-Jensen K., Guldberg P. Somatic Fas mutations in non-Hodgkin’s lymphoma: association with extranodal disease and autoimmunity. Blood, 92: 3018-3024, 1998.[Abstract/Free Full Text]
  15. Beltinger C., Kurz E., Böhler T., Schrappe M., Ludwig W. D., Debatin K. M. CD95 (Apo-1/Fas) mutations in childhood T-lineage acute lymphoblastic leukemia. Blood, 91: 3943-3951, 1998.[Abstract/Free Full Text]
  16. Lee S. H., Shin M. S., Park W. S., Kim S. Y., Dong S. M., Pi J. H., Lee H. K., Kim H. S., Jang J. J., Kim C. S., Kim S. H., Lee J. Y., Yoo N. J. Alterations of Fas (Apo-1/CD95) gene in transitional cell carcinomas of urinary bladder. Cancer Res., 59: 3068-3072, 1999.[Abstract/Free Full Text]
  17. Lee S. H., Shin M. S., Park W. S., Kim S. Y., Kim H. S., Han J. Y., Park G. S., Dong S. M., Pi J. H., Kim C. S., Kim S. H., Lee J. Y., Yoo N. J. Alterations of Fas (Apo-1/CD95) gene in non-small cell lung cancer. Oncogene, 18: 3754-3760, 1999.[Medline]
  18. Müschen M., Warskulat U., Beckmann M. W. Defining CD95 as a tumor suppressor gene. J. Mol. Med., 78: 312-325, 2000.[Medline]
  19. Cascino I., Paoff G., De Maria R., Testi R., Ruberti G. Fas/Apo-1 (CD95) receptor lacking the intracytoplasmic signaling domain protects tumor cells from Fas-mediated apoptosis. J. Immunol., 156: 13-17, 1996.[Abstract]
  20. Re D., Hofmann A., Wolf J., Diehl V., Staratschek-Jox A. Cultivated H/RS cells are resistant to CD95L-mediated apoptosis despite expression of wild-type CD95. Exp. Hematol., 28: 31-35, 2000.
  21. Jungnickel B., Staratschek-Jox A., Bräuninger A., Spieker T., Wolf J., Diehl V., Hansmann M. L., Rajewsky K., Küppers R. Clonal deleterious mutations in the I{kappa}B{alpha} gene in the malignant cells in Hodgkin’s lymphoma. J. Exp. Med., 191: 395-401, 2000.[Abstract/Free Full Text]
  22. Zhang L., Cui X., Schmitt K., Hubert R., Navidi W., Arnheim N. Whole genome amplification of a single cell: implication for genetic analysis. Proc. Natl. Acad. Sci. USA, 89: 5847-5851, 1992.[Abstract/Free Full Text]
  23. Müller M., Wilder S., Bannasch D., Israeli D., Lehlbach K., Li-Weber M., Friedmann S. L., Galle P. R., Stremmel W., Oren M., Krammer P. H. p53 activates the CD95 (Apo-1/Fas) gene in response to DNA damage by anticancer drugs. J. Exp. Med., 188: 2033-2045, 1998.[Abstract/Free Full Text]
  24. Montesinos-Rongen M., Roers A., Küppers R., Rajewsky K., Hansmann M. L. Mutation of the p53 gene is not a typical feature of Hodgkin and Reed-Sternberg cells in Hodgkin’s disease. Blood, 93: 1755-1760, 1999.
  25. Gravel S., Delsol G. , and Al Saati, T. Single cell analysis of the t(14, 18)(q31,q21)chromosomaltranslocationinHodgkin’sdiseasedemonstratestheabsenceofthisrearrangementinneoplasticHodgkinandReed-Sternbergcells.Blood,91: 2866-2874, 1998.
  26. Metkar S. S., Naresh K. N., Redkar A. A., Soman C. S., Advani S. H., Nadkarni J. J. Expression of Fas and Fas ligand in Hodgkin’s disease. Leuk. Lymphoma, 33: 521-530, 1999.[Medline]
  27. Fearon E. R., Vogelstein B. A genetic model for colorectal tumorigenesis. Cell, 61: 759-767, 1990.[Medline]



This article has been cited by other articles:


Home page
 J. Virol.Home page
M. T. Bolisetty, G. Dy, W. Tam, and K. L. Beemon
Reticuloendotheliosis Virus Strain T Induces miR-155, Which Targets JARID2 and Promotes Cell Survival
J. Virol., December 1, 2009; 83(23): 12009 - 12017.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Pathol.Home page
G Kapatai and P Murray
Contribution of the Epstein Barr virus to the molecular pathogenesis of Hodgkin lymphoma
J. Clin. Pathol., December 1, 2007; 60(12): 1342 - 1349.
[Abstract] [Full Text] [PDF]

Home page
 JCOHome page
D. Re, R. Kuppers, and V. Diehl
Molecular Pathogenesis of Hodgkin's Lymphoma
J. Clin. Oncol., September 10, 2005; 23(26): 6379 - 6386.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
A. Dutton, J. D. O'Neil, A. E. Milner, G. M. Reynolds, J. Starczynski, J. Crocker, L. S. Young, and P. G. Murray
Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin's lymphoma cells from autonomous Fas-mediated death
PNAS, April 27, 2004; 101(17): 6611 - 6616.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Re, P. Starostik, N. Massoudi, A. Staratschek-Jox, V. Dries, R. K. Thomas, V. Diehl, and J. Wolf
Allelic Losses on Chromosome 6q25 in Hodgkin and Reed Sternberg Cells
Cancer Res., May 15, 2003; 63(10): 2606 - 2609.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
M. Sanchez-Beato, A. Sanchez-Aguilera, and M. A. Piris
Cell cycle deregulation in B-cell lymphomas
Blood, February 15, 2003; 101(4): 1220 - 1235.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
E. M. Maggio, A. van den Berg, D. de Jong, A. Diepstra, and S. Poppema
Low Frequency of FAS Mutations in Reed-Sternberg Cells of Hodgkin's Lymphoma
Am. J. Pathol., January 1, 2003; 162(1): 29 - 35.
[Abstract] [Full Text] [PDF]

Home page
 ASH Education BookHome page
V. Diehl, H. Stein, M. Hummel, R. Zollinger, and J. M. Connors
Hodgkin's Lymphoma: Biology and Treatment Strategies for Primary, Refractory, and Relapsed Disease
Hematology, January 1, 2003; 2003(1): 225 - 247.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
L. Shen, A. C. T. Liang, L. Lu, W. Y. Au, Y.-L. Kwong, R. H. S. Liang, and G. Srivastava
Frequent Deletion of Fas Gene Sequences Encoding Death and Transmembrane Domains in Nasal Natural Killer/T-Cell Lymphoma
Am. J. Pathol., December 1, 2002; 161(6): 2123 - 2131.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
N. A. Mitchison and J. Roes
Patterned variation in murine MHC promoters
PNAS, August 6, 2002; 99(16): 10561 - 10566.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
R. K. Thomas, A. Kallenborn, C. Wickenhauser, J. L. Schultze, A. Draube, M. Vockerodt, D. Re, V. Diehl, and J. Wolf
Constitutive Expression of c-FLIP in Hodgkin and Reed-Sternberg Cells
Am. J. Pathol., April 1, 2002; 160(4): 1521 - 1528.
[Abstract] [Full Text] [PDF]

Home page
 BloodHome page
A. van den Berg, E. Maggio, A. Diepstra, D. de Jong, J. van Krieken, and S. Poppema
Germline FAS gene mutation in a case of ALPS and NLP Hodgkin lymphoma
Blood, February 15, 2002; 99(4): 1492 - 1494.
[Abstract] [Full Text] [PDF]

Home page
 JEMHome page
M. Muschen, D. Re, B. Jungnickel, V. Diehl, K. Rajewsky, and R. Kuppers
Somatic Mutation of the Cd95 Gene in Human B Cells as a Side-Effect of the Germinal Center Reaction
J. Exp. Med., December 18, 2000; 192(12): 1833 - 1840.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Müschen, M.
Right arrow Articles by Rajewsky, K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Müschen, M.
Right arrow Articles by Rajewsky, K.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online