Chronic myeloid leukemic cells trigger poly(ADP-ribose) polymerase-dependent inactivation and cell death in lymphocytes.
NK cells and T cells are commonly dysfunctional in CML, and their status may determine the course of disease. We aimed to define the molecular mechanisms of leukemia-induced immunosuppression with focus on the role of ROS and the PARP-1 pathway of cell death. Malignant granulocytes from patients with BCR-ABL-positive CML expressed the oxygen radical-producing enzyme NOX, produced large amounts of ROS, and triggered extensive cell death in NK cells. Inhibition of PARP-1 maintained NK cell viability in cocultures with suppressive leukemic cells. Under conditions of oxidative stress, PARP-1 inhibition upheld the capacity of NK cells to kill myeloid leukemic cells, in addition to restoring the proliferation and cytokine production of NK cells and cytotoxic T cells. Our findings are suggestive of a novel pathway of relevance to immunosuppression in CML.
University of Gothenburg, Göteborg, Sweden.
Johan
J
Aurelius
Anna
A
Martner
Rebecca E
RE
Riise
Ana I
AI
Romero
Lars
L
Palmqvist
Mats
M
Brune
Kristoffer
K
Hellstrand
Fredrik B
FB
Thorén
D016923:Cell Death; D018920:Coculture Techniques; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000276:immunology / Q000378:metabolism*; D018384:Oxidative Stress / Q000276:immunology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*
D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases