Myeloid cell leukaemia 1 has a vital role in retinoic acid‐mediated protection of T oll‐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 ( TLR 9) 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 ( MCL 1) at the transcriptional level, and knock down of MCL 1 by small interfering RNA partially reversed the effects of RA . To ensure that the combination of TLR 9‐ligands and RA would not promote the survival of malignant B cells, the combined effects of stimulation with RA and TLR 9 ligands was assessed on cells from patients with B‐cell malignancies. In contrast to the effects on normal B cells, the combination of TLR 9 stimulation and RA neither enhanced the MCL 1 levels nor inhibited the death of malignant B cells challenged by DNA ‐damaging agents. Taken together, the present results reveal a vital role of MCL 1 in RA ‐mediated survival of normal B cells. Moreover, the findings suggest that RA in combination with TLR 9 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.