In B-chronic lymphocytic leukemia (B-CLL), mature CD5+ B cells accumulate because of a defective apoptosis that causes an extended cell survival. These cells are the pro] eny of a pool (albeit small) of proliferating elements that feed the downstream accumulating compartment. We have asked which molecular mechanisms govern the proliferating pool, how they relate to apoptosis and which is the role of the microenvironment. We investig ited the expression of the family of Inhibitor of Apoptosis Proteins (IAP). lAPs are known to suppress apoptosis through caspase and pro-caspase inhibition, representing the last chance for a cell to escape its apoptotic fate. We analysed IAP expression in mononuclear cells from PB or BM of 30 B-CLL patients. Among the tested genes cIAPl, cIAP2, N AIP and XIAP were consistently positive in all the samples analysed. On the contrary, Survivin expression was undetectable in the majority of cases (25/30, 83%). We next considérée the possibility that physiological stimuli available to B cells in the microenvironment m ght modulate IAP expression. Since CD4+ T cells are present in involved BM and lymph nodes (LN), we focused our attention upon CD40 ligand (CD40L), expressed by activ ited T lymphocytes. We cultured B-CLL cells in vitro in the presence of soluble CD40L. The expression of cIAPl, cIAP2, NAIP and XIAP remained unmodified, while Survivin expression was upregulated after 48-96 hours of stimulation. We then evaluatec by immunohistochemistry the in vivo Survivin expression in LN and BM biopsies. In reactive LN, Survivin was detected only in highly proliferating Germinal Center (GC) cells, negi live for Bcl-2. In LN from B-CLL patients, Survivin was detected only in pseudofollicles where Survivin+ cells were actively proliferating and, in contrast with Survivin+ B cells found in normal GC, were Bcl-2+. In B-CLL BM biopsies, CD5+, Survivin+ cells were observed in clusters interspersed with T cells. These observations indicate that Sunivin controls the B-CLL proliferative pool and its ability to nourish the accumulation compartment, interfacing apoptosis. In addition Survivin expression may be modulated by microenvironmental stimuli, namely CD40/CD40L interaction.
|Issue number||11 PART I|
|Publication status||Published - 2000|
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