Panobinostat, a Pan-HDAC Inhibitor, Substantially Decreases the Quiescent Population of Leukemic Cells either in Monoculture or in Co-culture with Bone Marrow Stromal Cells.

Abstract

Background: It is increasingly evident that interactions between leukemic cells and their niches can have profound effects on clinical outcomes and have been contributed to the failure in treatment and drug shortage in the eradication of minimal residual disease, at least in part, through moving the cells from proliferative state to quiescent state. Objectives: We, therefore, investigated the effects of different bone marrow stromal cells (BMSCs) on the induction of quiescence and tested the advantage of pan-HDAC inhibitor panobinostat in the induction of apoptosis and targeting the quiescence cells of APL-derived (NB4) and CML-derived (K562) cell lines. Methods: We firstly evaluated the effect of BMSCs including mesenchymal stem cell (MSC), osteoblast, and macrophage on the induction of NB4 and K562 cells quiescence in co-culture models. Next, the alterations in mRNA expression of quiescence-related genes and leukemia-driver oncogenes were evaluated in different models. Finally, the anti-leukemic effects of panobinostat were evaluated, using MTT assay and evaluation of apoptosis and G0 population. Results: Upon 10 days of co-culture with stromal cells, we found that leukemic cells significantly accumulated in the G0 phase. The co-cultured cells also depictured an overall overexpression of most quiescence promoter genes. The oncogenes were underexpressed in the majority of co-cultured models. The results also showed that although panobinostat could induce apoptosis in co-cultured cells, its effect on the reduction of the G0 population was more striking. Conclusions: These data propose that leukemia cells' quiescence state induced by stromal cells is reversible by HDAC inhibition and panobinostat could be a potentiate drug for eradication of treatment-resistance quiescence leukemic cells.