Understanding life and death decisions in human leukaemias.

Human leukaemia cells have an often unique ability to either undergo apoptotic cell death mechanisms or, at other times, undergo proliferative expansion, sometimes to the same stimulus such as the pluripotent cytokine TNFα (tumour necrosis factor α). This potential for life/death switching helps us to understand the molecular signalling machinery that underlies these cellular processes. Furthermore, looking at the involvement of these switching signalling pathways that may be aberrant in leukaemia informs us of their importance in cancer tumorigenesis and how they may be targeted pharmacologically to treat various types of human leukaemias. Furthermore, these important pathways may play a crucial role in acquired chemotherapy resistance and should be studied further to overcome in the clinic many drug-resistant forms of blood cancers. In the present article, we uncover the relationship that exists in human leukaemia life/death switching between the anti-apoptotic pro-inflammatory transcription factor NF-κB (nuclear factor κB) and the cytoprotective antioxidant-responsive transcription factor Nrf2 (nuclear factor-erythroid 2-related factor 2). We also discuss recent findings that reveal a major role for Btk (Bruton's tyrosine kinase) in both lymphocytic and myeloid forms of human leukaemias and lymphomas.

The high Nrf2 expression in human acute myeloid leukemia is driven by NF-κB and underlies its chemo-resistance.

NF-E2-related factor 2 (Nrf2) transcription factor regulates a range of cytoprotective transcriptional responses, preventing further cellular injury by removing biochemical damage and renewing tissue. Here we show that acute myeloid leukemia (AML) cells possess greater constitutive nuclear levels of Nrf2 than normal control CD34(+) cells because of an imbalance between mRNA expression levels of Nrf2 and its inhibitor Keap1 but not through their somatic mutation. Elevated Nrf2 was reduced by NF-κB inhibitors. Using promoter assays, ChIP and siRNA knockdown, we demonstrated NF-κB subunits p50 and p65 induce transcription of Nrf2 in AML cells at a specific promoter κB-site and that long-term lentiviral miRNA-knockdown of Nrf2 significantly reduced clonogenicity of AML patient cells and improved their chemotherapeutic responsiveness. Normal physiologic Nrf2 protects cells from damage, but here we have exposed aberrant continuous nuclear activation of Nrf2 in AML that allows cell survival, even against cytotoxic chemotherapeutics. We show for the first time that Nrf2, an important regulator of several biologic processes involved in the progression of cancer, has abnormal NF-κB-driven constitutive expression in AML. Such a mechanism allows for a greater cytoprotective response in human AML cells and encourages their evasion of chemotherapy-induced cytotoxicity, which is necessary for improved clinical outcomes.

Understanding the role of NRF2-regulated miRNAs in human malignancies.

Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a key transcription factor that regulates the expression of over a hundred cytoprotective and antioxidant genes that provide cellular protection from reactive oxygen species. Chemotherapy resistance in several cancers has been linked to dysregulation of the NRF2 signalling pathway, moreover there is growing evidence that NRF2 may contribute to tumorigenesis. MicroRNA (miRNA) are small non-coding RNA sequences that post-transcriptionally regulate mRNA sequences. In cancer pathogenesis, aberrantly expressed miRNAs can act as either tumor suppressor or oncogenic miRNA. Recent evidence has been described that identifies a number of miRNA that can be regulated by NRF2. This review outlines the importance of NRF2 in regulating miRNA, and the functional role this may have in the tumorigenesis of human malignancies and their chemotherapy resistance.