Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets

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BlankAberrantly activated anti-apoptotic signalling mechanisms in chronic

lymphocytic leukaemia cells: clues to the identification of novel therapeutic

targets.

R Gitendra Wickremasinghe, AG Prentice, and AJ Steele

Br J Haematol, April 18, 2011; .

Department of Haematology, Cancer Institute, University College Hospital Medical

School, London, UK.

Chronic lymphocytic leukaemia (CLL) is the commonest haematological malignancy

in the western world and is incurable by cytotoxic therapy. Considerable

research effort has identified the signal transduction pathways in CLL cells

that contribute to anti-apoptotic signalling. Some pathways are constitutively

activated in CLL cells but upregulated in normal cells only when protein

tyrosine kinases (PTKs) are activated by ligands. This review describes which

PTKs are aberrantly activated in CLL cells and are potential targets for

inhibition. Additional potential targets within pathways downstream of these

PTKs include Mek/Erk, mTorc1, protein kinase C, PI-3 kinase/Akt, nuclear

factor-?B and cyclin-dependent protein kinase. Numerous studies have identified

chemical agents and antibodies that selectively kill CLL cells, irrespective of

their genetic resistance to conventional chemotherapeutic agents, and which can

overcome cytoprotective microenvironmental signalling. These studies have

resulted in identification of novel therapies, some of which are currently

undergoing clinical trials. In vitro and animal model studies and clinical

trials could determine which inhibitors of which targets are the likely to be

most effective and least toxic either singly or in combination.

PMID: 21501136