Antiapoptotic microenvironment of acute myeloid leukemia.
We showed previously that tumor-derived supernatant (TSN) from acute myeloid leukemia (AML) myeloblasts inhibits peripheral blood T cell activation and proliferation, rendering the T cells functionally incompetent. We show here that the AML TSN also significantly delays apoptosis of both resting and stimulated T cells, as judged by reduction in annexin V/propidium iodide staining. In addition, we show that this is not unique to T cells and that AML TSN inhibits apoptosis of peripheral B cells, neutrophils, and monocytes. Furthermore, it also enhances the survival of other AML myeloblasts with lower viability. Investigations into the mechanism demonstrate a reduction in the cleavage of procaspase-3, -8, and -9 and the caspase substrate, poly(ADP-ribose)polymerase (PARP). This may be due to Bcl-2, which is normally down-regulated in CD3/CD28-stimulated T cells, but is maintained in the presence of AML TSN. We conclude that AML cells generate an antiapoptotic microenvironment that favors the survival of malignant cells, but also inhibits apoptosis of other normal hemopoietic cells. Reversal of these immunosuppressive effects and restoration of normal immune responses in patients with AML would improve the success of immunotherapy protocols.
Milojkovic
Dragana
D
Department of Haematological Medicine, Leukaemia Sciences, Guy's, King's and St. Thomas' School of Medicine, Rayne Institute, London, United Kingdom. dragana.milojkovic@kcl.ac.uk
Devereux
Stephen
S
Westwood
Nigel B
NB
Mufti
Ghulam J
GJ
Thomas
N Shaun B
NS
Buggins
Andrea G S
AG
D000208:Acute Disease; D017209:Apoptosis / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D001402:B-Lymphocytes / Q000166:cytology; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002474:Cell-Free System / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004268:DNA-Binding Proteins; D006801:Humans; D007951:Leukemia, Myeloid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D009000:Monocytes / Q000166:cytology; D009504:Neutrophils / Q000166:cytology; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein
D051017:Apoptosis Regulatory Proteins; C091732:BCL2-associated athanogene 1 protein; C494811:BCL2L1 protein, human; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; D002352:Carrier Proteins; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D051020:bcl-X Protein