Myeloid cell leukaemia 1 has a vital role in retinoic acid-mediated protection of Toll-like receptor 9-stimulated B cells from spontaneous and DNA damage-induced apoptosis.
Vitamin A is an essential anti-infective agent with pleiotropic effects on cells of the immune system. The goal of the present study was to unravel the impact of the vitamin A metabolite retinoic acid (RA) on B-cell survival related both to normal B-cell homeostasis and to the detrimental effects imposed by DNA-damaging agents. By combining RA with Toll-like receptor 9 (TLR9) ligands, we show that RA prevents spontaneous, irradiation- and doxorubicin-induced apoptosis of human B cells in an RA receptor-dependent manner. RA-mediated survival involved up-regulation of the anti-apoptotic protein myeloid cell leukemia 1 (MCL1) at the transcriptional level, and knock down of MCL1 by small interfering RNA partially reversed the effects of RA. To ensure that the combination of TLR9-ligands and RA would not promote the survival of malignant B cells, the combined effects of stimulation with RA and TLR9 ligands was assessed on cells from patients with B-cell malignancies. In contrast to the effects on normal B cells, the combination of TLR9 stimulation and RA neither enhanced the MCL1 levels nor inhibited the death of malignant B cells challenged by DNA-damaging agents. Taken together, the present results reveal a vital role of MCL1 in RA-mediated survival of normal B cells. Moreover, the findings suggest that RA in combination with TLR9 ligands might be useful adjuvants in the treatment of B-cell malignancies by selectively protecting normal and not malignant B cells from DNA-damage-induced cell death.
Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, Oslo, Norway.
Kristine L
KL
Holm
Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, Oslo, Norway.
Randi L
RL
Indrevaer
Department of Immunology, Institute for Cancer Research, Oslo University Hospital HF, Montebello, Oslo, Norway.
June Helen
JH
Myklebust
Department of Oncology, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital HF, Montebello, Oslo, Norway.
Arne
A
Kolstad
Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, Oslo, Norway.
Jan Øivind
JØ
Moskaug
Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, Oslo, Norway.
Elin H
EH
Naderi
Department of Molecular Medicine, Institute of Basic Medical Science, University of Oslo, Oslo, Norway.
Heidi K
HK
Blomhoff
D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D004249:DNA Damage; D004317:Doxorubicin / Q000633:toxicity; D005260:Female; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D015448:Leukemia, B-Cell / Q000188:drug therapy* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011827:Radiation; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D014212:Tretinoin / Q000737:chemistry / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D014801:Vitamin A / Q000737:chemistry
D051217:Toll-Like Receptor 9; D014801:Vitamin A; D014212:Tretinoin; D004317:Doxorubicin
B cells; Toll like receptor 9; apoptosis; myeloid cell leukaemia 1; retinoic acid