Molecular mechanisms of hematopoietic differentiation by valproic acid and lithium

This work addresses the molecular targets of lithium and valproic acid in the induction of leukemia cell differentiation. Valproic acid (VPA), a common therapy for epilepsy and bipolar disorder, has been recently identified in our laboratory as a histone deacetylase (HDAC) inhibitor. We have studied the in vitro inhibition of class I and II HDACs by VPA, and established that valproic acid is a more specific inhibitor compared with some other commonly used HDAC inhibitors. We have then used structural analogs of VPA to establish a correlation between in vitro inhibition of HDACs and induction of differentiation in leukemia cells. The results suggest that inhibition of HDACs is responsible for the induction of differentiation by VPA, and that valproic acid is a promising candidate for treatment of leukemias and potentially other malignancies. Lithium, a drug commonly used for treatment of bipolar disorder, is a direct inhibitor of glycogen synthase kinase-3 (GSK3), a negative regulator of the Wnt and insulin pathways. One of the side effects of lithium treatment is an increase in white blood cell counts, so we hypothesized that this effect could be due to an effect of lithium on hematopoietic stem cell fate. Lithium induces myeloid differentiation of leukemic cells, and we have investigated whether inhibition of GSK3 and subsequent activation of the Wnt pathway mediates these effects of lithium. The results suggest that activation of the Wnt pathway is not involved, whereas inhibition of GSK3 may be involved in the induction of differentiation of leukemia cells by lithium