Recent advances in elucidating KEAP1-NRF2 functions in hematopoietic/immune cells and leukemic cells
Shohei Murakami1, Hozumi Motohashi
1Department of Gene Expression Regulation in Institute of Development, Aging and Cancer, Tohoku University.
Abstract:
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.
Insights
The KEAP1-NRF2 system regulates cytoprotective genes and influences cell fate in hematopoietic cells. NRF2 activators and inhibitors show promise for treating inflammation and leukemia.
Area of Science:
- Molecular Biology
- Cell Biology
- Biochemistry
Background:
- The KEAP1-NRF2 system is a key regulator of cellular defense against oxidative stress and xenobiotics.
- NRF2 activation influences gene transcription involved in cell proliferation, differentiation, and homeostasis.
- NRF2 plays critical roles in hematopoietic stem cell maintenance and blood cell maturation.
Purpose of the Study:
- To explore the multifaceted roles of the KEAP1-NRF2 system in cellular processes.
- To investigate the implications of NRF2 activation in hematopoietic cells and inflammatory responses.
- To assess the therapeutic potential of NRF2 modulators in diseases like multiple sclerosis and leukemia.
Main Methods:
- Literature review and analysis of existing research on the KEAP1-NRF2 pathway.
- Examination of NRF2's role in gene expression and cellular functions.
- Discussion of clinical applications and therapeutic strategies involving NRF2.
Main Results:
- NRF2 activation enhances transcription of cytoprotective genes and impacts cell proliferation and differentiation.
- NRF2 is crucial for hematopoietic stem cell maintenance, megakaryocyte/erythrocyte homeostasis, and exhibits anti-inflammatory effects.
- Elevated NRF2 levels in acute myeloid leukemia confer resistance to anticancer drugs.
Conclusions:
- The KEAP1-NRF2 system is a critical regulator with dual roles in cellular health and disease.
- NRF2 activators (e.g., BG-12) are effective in treating inflammatory conditions like multiple sclerosis.
- NRF2 inhibitors represent a promising therapeutic strategy for overcoming drug resistance in leukemia.
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