Published in: Proc. Natl. Acad. Sci. USA, vol. 101, no. 17, pp. 6611-6616 (April 27, 2004).
Published online before print April 19, 2004, 10.1073/pnas.0400765101
http://www.pnas.org/cgi/content/abstract/101/17/6611?etoc

"Expression of the cellular FLICE-inhibitory protein (c-FLIP) protects Hodgkin's lymphoma cells from autonomous Fas-mediated death".

A. Dutton *, J. D. O'Neil 1, A. E. Milner 1, G. M. Reynolds 2, J. Starczynski 3 , J. Crocker 3 , L. S. Young 1,  and P. G. Murray * ¶

* Department of Pathology, 1 Cancer Research UK Institute for Cancer Studies, and 2 Liver Research Laboratories, University of Birmingham, Birmingham B15 2TT, United Kingdom; and
3 Department of Cellular Pathology, Birmingham Heartland's Hospital, Bordesley Green East, Birmingham B15 2TT, United Kingdom

¶ To whom correspondence should be addressed at: Department of Pathology, Division of Cancer Studies, Medical School, University of Birmingham, Edgbaston, Birmingham B15 2TT, United Kingdom.
E-mail:   p.g.murray@bham.ac.uk


Abstract:

Hodgkin's lymphoma (HL) is characterized by the presence of malignant so-called Hodgkin's/Reed-Sternberg (HRS) cells, which display resistance to certain apoptotic stimuli, including a lack of sensitivity to Fas-mediated cell death. However, the mechanisms responsible for their resistance to apoptosis inducers have not been elucidated. Here we confirm that both HL-derived cell lines and the HRS cells of primary HL tissues express Fas ligand (FasL) along with the inhibitory c-FLIP protein. Down-regulation of cellular FLICE (FADD-like IL-1b-converting enzyme)-inhibitory protein (c-FLIP) through the use of specific small inhibitory RNAs (siRNAs) leads to reduced viability of the L428 and L591 HL-derived cell lines. To determine whether endogenous FasL was responsible for the reduction in cell viability observed after down-regulation of c-FLIP, L428 and L591 cells were treated with c-FLIP-specific siRNAs with and without siRNAs directed to FasL. Treatment of these cells with both c-FLIP- and FasL-specific siRNAs in combination restored cell viability to near control levels. Our results provide a mechanism whereby HRS cells are protected from autonomous FasL-mediated cell death while preserving their ability to evade immunosurveillance. Targeting c-FLIP could provide a novel approach to the treatment of HL. 


Abbreviations: HRS cells, Hodgkin's/Reed-Sternberg cells; HL, Hodgkin's lymphoma; GC, germinal center; BCR, B cell receptor; DISC, death-inducing signaling complex; FasL, Fas ligand; c-FLIP, cellular homologue of FLICE-inhibitory protein; CHX, cycloheximide; siRNA, small interfering RNA. 

Additional References:

1. Frenster JH, Papalian MM, Masek MA and Frenster JA, "Electron Microscopic Analysis of Lymph Node Cellular Activity in Hodgkin's Disease", Journal of the National Cancer Institute, Vol. 63, pp. 331-335, Aug. 1979.

2. Archibald RB, and Frenster JH, "Quantitative Electron Microscopic Sector Analysis of Lymphocyte
Interactions with Reed-Sternberg Cells in Hodgkin's Disease", Proc. Am. Assoc. Cancer Res. 12: 43-44 (1971).

3. Frenster JH, "Electron Microscopic Localization of Acridine Orange Binding to DNA within Human Leukemic Bone Marrow Cells", Cancer Res. 31: 1128-1133 (1971).

4. Archibald RB, and Frenster JH, "Quantitative Ultrastructural Analysis of In-Vivo Lymphocyte - Reed-Sternberg Cell Interactions in Hodgkin's Disease", Natl. Cancer Inst. Monogr. 36: 239-245 (1973).

5. Masek MA, Rhoades DJ, and Frenster JH, "In-Vivo Macrophage Interactions with Lymphocytes in Hodgkin's Disease", Proc. Am. Assoc. Cancer Res. 14: 8 (1973).

6. Frenster JH,  and Herstein PR, "Gene De-Repression", New Eng. J. Med. 288: 1224-1229 (June 7, 1973).

7. Frenster JH, Nakatsu SL, and Masek MA, "Ultrastructural Probes of DNA Templates within Human Bone Marrow and Lymph Node Cells", Adv. Cell Molec. Biol. 3, 1-19 (1974).

8. Frenster JH, "Ultrastuctural Probes of Gene De-Repression within Human Leukemia and Lymphoma Cells", Proc. 11th International Cancer Congress, Florence, Italy (October, 1974).

9. Rowan RA, Masek MA, Thompson JM, and Frenster JH, "Electron Microscopic Localization of Acid Phosphatase Activity within Hodgkin's Disease Lymph Nodes", Proc. Am. Assoc. Cancer Res. 16: 10 (1975).

10. Frenster JH, "Analysis of Queueing and Renewal Systems in Hodgkin's Disease", Proc. Am. Assoc. Cancer Res. vol. 16: p. 223 (March, 1975).

11. Frenster JH, Landrum SR, Masek MA, and Wilson LS, "Nuclear Maturation Within Neoplastic Cells In-Vivo", J. Cell Biol. 67: 123a (1975).

12. Frenster JH, Landrum SR, Masek MA, et al, "Comparison of DNA Helix Openings during In-Vivo Mitosis of Normal and Neoplastic Human Cells", Proc. Am. Assoc. Cancer Res. 19, 1-2 (1978).

13. Frenster JA, Papalian MM, Masek MA, et al, "Persistent Euchromatin after DNA Template Inactivation", J. Cell Biol. 79, 110a-111a (1978).

14. Frenster JH, Papalian MM, Masek MA, and Frenster JA, "Asymmetry of Intra-Nuclear Function during Immune Lymphocyte Activation", Biophys. J. vol. 25, no. 2, part 2, p. 228a, Feb. 1979.

15. Frenster JH, Papalian MM, Masek MA and Frenster JA, "Electron Microscopic Analysis of Lymph Node Cellular Activity in Hodgkin's Disease", Journal of the National Cancer Institute, Vol. 63, pp. 331-335, Aug. 1979.

16. Frenster JH, "Single-Cell Analysis of DNase I-Sensitive Sites During Neoplastic Cell Differentiation within Hodgkin's Disease Lymph Nodes", Leukemia Reviews International, Rich MA, Editor, Volume 1, pp. 22-23, (Marcel Dekker, Inc. New York/1983).

17. Frenster JH, "Single-Cell Analysis of DNase I-Sensitive Sites during Neoplastic and Normal Cell Differentiation within Human Bone Marrow", Ann. N.Y. Acad. Sci. 567: 334-336 (Aug. 4, 1989).

18. Ruf IK, Rhyne PW, Yang C, Cleveland JL, and Sample JT, "Epstein-Barr Virus Small RNAs Potentiate Tumorigenicity of Burkitt Lymphoma Cells Independently of an Effect on Apoptosis", J. Virol. vol. 74, no. 21, pp. 10223-10228 (November, 2000).

19. Maruo S, Nanbo A, and Takada K, "Replacement of the Epstein-Barr Virus Plasmid with the EBER Plasmid in Burkitt's Lymphoma Cells", J. Virol. vol. 75, no. 20, pp. 9977-9982 (October, 2001).

20. Frenster JH, "Uni-Polar Clustering of Lymphocyte DNA Templates Toward Neoplastic Target Cells within Hodgkin's Disease Lymph Nodes", Proc. Am. Assoc. Cancer Res. vol. 43, p. 1134 (March, 2002).

21. Carella AM, "Stem Cell Transplantation for Hodgkin's Disease: A Review of the Literature", Clinical Lymphoma, vol. 2, no. 4, pp. 212-221 (March, 2002).

22. Childs RW, "Immunotherapy of Solid Tumors: Nonmyeloablative Allogeneic Stem Cell Transplantation", Advances in Cancer Treatment Newsletter, Medscape Hematology-Oncology eJournal 5(3), June, 2002.

23. Faulkner RD, Craddock C, Byrne JL, Mahendra P, Haynes AP, Prentice HG, Potter M, Pagliuca A, Ho A, Devereux S, McQuaker G, Mufti G, Yin JL, and Russell NH, "BEAM-Campath reduced intensity allogeneic stem cell transplantation for lymphoproliferative disease: GVHD, toxicity and survival in 65 patients". Blood First Edition Paper, prepublished online September 11, 2003; DOI 10.1182/blood-2003-05-1406.

24. Coughlin CM, Vance BA, Grupp SA, and Vonderheide RH, "RNA-transfected CD40-activated B cells induce functional T-cell responses against viral and tumor antigen targets: implications for pediatric immunotherapy", Blood First Edition Paper, prepublished online November 20, 2003;
DOI 10.1182/blood-2003-07-2379.

25. Murray PG, Qiu G-H, Fu L, Waites ER, Srivastava G, Heys D, Agathanggelou A, Latif F, Grundy RG, Mann JR, Starczynski J, Crocker J, Parkes SE, Ambinder RF, Young LS, and Tao Q, "Frequent epigenetic inactivation of the RASSF1A tumor suppressor gene in Hodgkin's lymphoma", Oncogene, vol. 23, no. 6, pp. 1326-1331 (February 2, 2004).

26. Su C-C, Chiu H-H, Chang C-C, Chen J-C, and Hsu S-M, "CD30 is Involved in Inhibition of T-Cell Proliferation by Hodgkin's Reed-Sternberg Cells", Cancer Research vol. 64, no. 6, pp. 2148-2152 (March 15, 2004).

27. Mathas S, Lietz A, Anagnostopoulos I, Hummel F, Wiesner B, Janz M, Jundt F, Hirsch B, Jöhrens-Leder K, Vornlocher H-P, Bommert K, Stein H, and Dörken B, "c-FLIP Mediates Resistance of Hodgkin/Reed-Sternberg Cells to Death Receptor–induced Apoptosis",  J. Exp. Med., vol. 199, no. 8, pp. 1041-1052 (April 19, 2004).

Further Topics in:  Euchromatin,  active DNA, and  RNA  ribo-regulators:

Reviews and Research:

Links to Euchromatin Activator RNA Reviews:
Links to Euchromatin Activator RNA Research:
Links to Ultrastructural Probes of DNase I-Sensitive Sites:
Links to RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma Immuno-Pathology:
Links to Activated T-Lymphocyte Immunotherapy:
Links to Medical Systems Biology:

"Ultrastructural Probes of Active DNA Sites, and the RNA Activators of DNA".


Top of Page - Euchromatin Network - Current Research - Forums - Other Sites - Future Events -

For Further Information and Feedback:
E-mail: frenster@euchromatin.net


euchromatin: "the most active portion of the genome within the cell nucleus".