Recent advances in elucidating KEAP1-NRF2 functions in hematopoietic/immune cells and leukemic cells.

The KEAP1-NRF2 system is an inducible molecular mechanism enhancing transcriptions of several cytoprotective genes in response to xenobiotics and oxidative stress. Recently, the KEAP1-NRF2 system has been suggested to directly regulate a portion of the genes related to cell proliferation and differentiation. In hematopoietic cells, NRF2 activation plays a role in maintenance and cell fate determination of hematopoietic stem cells, as well as in maturation processes and homeostasis of megakaryocytes and erythrocytes. In addition, NRF2 activation has been reported to suppress the production and secretion of inflammatory cytokines, thereby exerting anti-inflammatory effects. An NRF2 inducer, BG-12, was recently approved as a drug for multiple sclerosis. In contrast, in acute myeloid leukemia, the leukemia cells reportedly have higher NRF2 mRNA levels that lead to an increase in NRF2 protein abundance, by which these cells acquire high resistance to anticancer drugs. Therefore, both NRF2 activators and inhibitors are promising agents for the development of effective therapies for chronic inflammation and leukemia, respectively.