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

Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets
Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets
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.
chronic lymphocytic leukaemia, apoptosis, chronic lymphocytic leukaemia drug sensitivity, trials, protein phosphorylation
0007-1048
Gitendra Wickremasinghe, R.
9250eac5-84c1-4f53-9f7d-fb3d7cb2a446
Prentice, Archibald G.
a834a471-b816-4c3a-a3d4-70fa8dd2c982
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089
Gitendra Wickremasinghe, R.
9250eac5-84c1-4f53-9f7d-fb3d7cb2a446
Prentice, Archibald G.
a834a471-b816-4c3a-a3d4-70fa8dd2c982
Steele, Andrew J.
4349f6aa-2e3a-49a8-be73-7716056ae089

Gitendra Wickremasinghe, R., Prentice, Archibald G. and Steele, Andrew J. (2011) Aberrantly activated anti-apoptotic signalling mechanisms in chronic lymphocytic leukaemia cells: clues to the identification of novel therapeutic targets. British Journal of Haematology. (doi:10.1111/j.1365-2141.2011.08676.x). (PMID:21501136)

Record type: Article

Abstract

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.

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More information

Published date: 18 April 2011
Keywords: chronic lymphocytic leukaemia, apoptosis, chronic lymphocytic leukaemia drug sensitivity, trials, protein phosphorylation

Identifiers

Local EPrints ID: 182957
URI: http://eprints.soton.ac.uk/id/eprint/182957
ISSN: 0007-1048
PURE UUID: 2595d84e-e837-4063-9ec6-bd2ade4a17f6
ORCID for Andrew J. Steele: ORCID iD orcid.org/0000-0003-0667-1596

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Date deposited: 28 Apr 2011 11:54
Last modified: 15 Mar 2024 03:39

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Contributors

Author: R. Gitendra Wickremasinghe
Author: Archibald G. Prentice

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