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Blood, 15 March 2006, Vol. 107, No. 6, pp. 2544-2547.
Prepublished online as a Blood First Edition Paper on November 22, 2005; DOI 10.1182/blood-2005-06-2601.
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Submitted July 1, 2005
Accepted November 6, 2005
c-Flip confers resistance to fas-mediated apoptosis in anaplastic large cell lymphoma
Mauricio P Oyarzo, L. Jeffrey Medeiros, Coralyn Atwell, Marianna Feretzaki, Vasiliki Leventaki, Elias Drakos, Hesham M Amin, and George Z Rassidakis*
Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA
* Corresponding author; email: gzrassidakis{at}mdanderson.org.
We hypothesized that inhibition of the FAS-mediated apoptosis pathway by FLICE-like inhibitory protein (c-FLIP) may contribute to oncogenesis in ALK+ anaplastic large cell lymphoma (ALCL). Treatment with increasing concentrations of CH-11 (CD95/Fas agonistic antibody) had no effect on cell viability of two ALK+ ALCL cell lines, Karpas 299 and SU-DHL1, each expressing high levels of c-FLIP. However, inhibition of endogenous c-FLIP expression by specific c-FLIP siRNA in Karpas 299 and SU-DHL1 cells treated with CH-11 resulted in FAS-mediated cell death associated with increased annexin V binding, apoptotic morphology and cleavage of caspase 8. In 26 ALK+ ALCL tumors, assessed for expression of DISC-associated proteins, CD95/Fas and c-FLIP were commonly expressed, in 23/25 (92%) and 21/23 (91%) tumors, respectively. By contrast, CD95L/FasL was expressed in only 3/26 (12%) ALCL although it was strongly expressed by surrounding small reactive lymphocytes. Our findings suggest that overexpression of c-FLIP protects ALK+ ALCL cells from death-receptor induced apoptosis and may contribute to ALCL pathogenesis.
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