1. ¹Department of Hematology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
2. ²Laboratory for Experimental Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
3. ³John and Rebecca Moores Cancer Center, University of California at San Diego, La Jolla, CA, USA
4. ⁴Department of Clinical Viro-immunology, Sanquin Research at CLB, Amsterdam, The Netherlands
5. ⁵Department of Internal Medicine, Meander Medical Center, Amersfoort, The Netherlands

Correspondence: Dr E Eldering, Laboratory of Experimental Immunology, Academic Medical Center, L1-106, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands. Fax: +31 20 566 97 56; E-mail: e.eldering@amc.uva.nl

⁶These authors contributed equally to this work.

Received 3 August 2004; Accepted 8 November 2004; Published online 20 January 2005.

Abstract

We investigated the apoptosis gene expression profile of chronic lymphocytic leukemia (CLL) cells in relation to (1) normal peripheral and tonsillar B-cell subsets, (2) IgV_H mutation status, and (3) effects of cytotoxic drugs. In accord with their noncycling, antiapoptotic status in vivo, CLL cells displayed high constitutive expression of Bcl-2 and Flip mRNA, while Survivin, Bid and Bik were absent. Paradoxically, along with these antiapoptotic genes CLL cells had high-level expression of proapoptotic BH3-only proteins Bmf and Noxa. Treatment of CLL cells with fludarabine induced only the proapoptotic genes Bax and Puma in a p53-dependent manner. Interestingly, the degree of Puma induction was more pronounced in cells with mutated IgV_H genes. Thus, disturbed apoptosis in CLL is the net result of both protective and sensitizing aberrations. This delicate balance can be tipped via induction of Puma in a p53-dependent matter, the level of which may vary between groups of patients with a different tendency for disease progression.