Biochemical Society Transactions

Signalling and Acquired Resistance to Targeted Cancer Therapeutics

Understanding life and death decisions in human leukaemias

David J. MacEwan, Lawrence N. Barrera, Sujitra Keadsanti, Stuart A. Rushworth, Niraj M. Shah, Tianma Yuan, Lyubov Zaitseva


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.

  • acute myeloid leukaemia (AML)
  • anti-apoptotic agent
  • Bruton’s tyrosine kinase (Btk)
  • cytoprotective gene
  • life/death switching
  • transcription factor


  • Signalling and Acquired Resistance to Targeted Cancer Therapeutics: A Biochemical Society Focused Meeting held at Robinson College, Cambridge, U.K., 5–7 January 2014. Organized and Edited by Jim Caunt (University of Bath, U.K.), Simon Cook (Babraham Institute, Cambridge, U.K.) and David MacEwan (University of Liverpool, U.K.).

Abbreviations: AML, acute myeloid leukaemia; Btk, Bruton’s tyrosine kinase; CLL, chronic lymphocytic leukaemia; FLICE, FADD (Fas-associated death domain)-like IL-1β-converting enzyme; FLIP, FLICE-inhibitory protein; HO-1, haem oxygenase 1; HSC, haemopoietic stem cell; IL, interleukin; MCL, mantle cell lymphoma; MM, multiple myeloma; NF-κB, nuclear factor κB; Nrf2, nuclear factor-erythroid 2-related factor 2; TNF, tumour necrosis factor; TNFR, TNF receptor

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