CD160 signaling mediates PI3K-dependent survival and growth signals in chronic lymphocytic leukemia.
B-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.
Liu
Feng-Ting
FT
Academic Haematology Unit, Blizard Institute of Cell and Molecular Science, Queen Mary University of London, London, United Kingdom.
Giustiniani
Jerome
J
Farren
Timothy
T
Jia
Li
L
Bensussan
Armand
A
Gribben
John G
JG
Agrawal
Samir G
SG
D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D049109:Cell Proliferation; D002470:Cell Survival; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D005260:Female; D058851:GPI-Linked Proteins; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000201:enzymology* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D051336:Mitochondrial Membranes / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism*; D015398:Signal Transduction
D015703:Antigens, CD; C114505:CD160 protein, human; D058851:GPI-Linked Proteins; D015850:Interleukin-6; D016209:Interleukin-8; D019253:Proto-Oncogene Proteins c-bcl-2; D011971:Receptors, Immunologic; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020169:Caspases