Regulation of death receptor-mediated apoptosis in B cell malignancies

Abstract

To examine the biological function of death receptors in B cell malignancies, the responsiveness to Fas- and TRAIL receptor-induced apoptosis was determined in a panel of Burkitt lymphoma (BL) cell lines including Epstein-Barr virus negative and positive lines with type I, II and III latency programmes.  The patterns of resistance to either signal differed between distinct groups of BL cell lines and in some cases resistance was independent of the levels of receptor expressed.  I examined the role of molecular determinants that modulate death receptor-mediated apoptosis in other cell systems, receptor mutations and the expression of FADD, caspase 8, decoy and soluble receptors as well as the signalling inhibitors FLIPL and FAP-1.  However, these did not correlate with the observed patterns of sensitivity in BL. Therefore novel mechanisms may underlie resistance to death receptor-induced apoptosis in these cells.  Death receptors have also been implicated in apoptosis induced by chemotherapeutic agents.  Although BL cell lines readily underwent apoptosis when treated with the DNA-damaging drug, CDDP, there was no evidence for a major role of Fas and TRAIL receptors in CDDP-induced apoptosis of a BL cell line containing wild type p53.

To compare the results from BL cell lines with primary B cells, the responsiveness to death receptor-mediated apoptosis was also tested in ex vivo chronic lymphocytic leukaemia (CLL) cells.  The majority of CLL cells analysed were susceptible to spontaneous apoptosis in vitro, a significant number was sensitive to Fas-induced apoptosis whereas the entire cell panel were resistant to TRAIL-induced apoptosis. Resistance to TRAIL- and in some cases to Fas-induced apoptosis was receptor-independent consistently with the observations in BL cell lines.

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