CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia

Author:

Liu Feng-Ting1,Giustiniani Jerome123,Farren Timothy14,Jia Li5,Bensussan Armand3,Gribben John G.45,Agrawal Samir G.14

Affiliation:

1. Academic Haematology Unit, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, United Kingdom;

2. Laboratoire de Thérapie Cellulaire, Institut Jean Godinot, Reims, France;

3. Inserm U976 and University Denis Diderot-Paris 7, Saint Louis Hospital, Paris, France; and

4. Department of Haemato-Oncology and

5. Institute of Cancer, Cancer Research UK, Queen Mary University of London and Barts and the London National Health Service (NHS) Trust, London, United Kingdom

Abstract

AbstractB-cell chronic lymphocytic leukemia (CLL) expresses CD160, a glycosylphosphatidylinositol-linked receptor found on normal natural killer (NK) and T cells, but not B cells. CD160 is a multifunctional molecule in normal lymphocytes, but its role in CLL biology is unknown. In vitro, CLL cells undergo rapid spontaneous apoptosis, which CD160 activation protected against—mean cell viability increased from 67% to 79% (P < .001). This was associated with up-regulation of Bcl-2, Bcl-xL, and Mcl-1, but not Bax. As expected from these changes in Bcl-2/Bax and Bcl-xL/Bax ratios, CD160 triggering reduced mitochondrial membrane potential collapse and cytochrome c release. CD160 stimulation also induced DNA synthesis, cell cycle progression, and proliferation. B-cell antigen receptor (BCR)–induced CLL proliferation was generally greater than with CD160, but marked variation was seen. Both BCR and CD160 signaling led to CLL secretion of interleukin-6 (IL-6) and IL-8, although CD160 induced greater increases of IL-6 (51-fold) and IL-8 (15-fold). Survival and activation signals mediated by CD160 showed dose-dependent suppression by phosphoinositide-3 kinase (PI3K) inhibitors. Thus, in vitro, CLL cells can use the CD160 pathway for survival and activation, mimicking CD160 signaling in normal NK and CD8+ T cells. Establishing the pathophysiologic relevance of these findings may reveal new therapeutic targets.

Publisher

American Society of Hematology

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