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Carcinogenesis Advance Access published online on December 5, 2006
Carcinogenesis, doi:10.1093/carcin/bgl235
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

DHFR and MSH3 co amplification in childhood acute lymphoblastic leukaemia, in vitro and in vivo

Elizabeth C. Matheson, Linda A. Hogarth, Marian C. Case, Julie A. E. Irving and Andrew G. Hall

Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom.

Corresponding author: Andrew Hall, Northern Institute for Cancer Research, Paul O'Gorman Building, Medical School, Newcastle, NE2 4HH, UK. Tel: +44 191 246 4411, Fax: +44 191 246 4301. e-mail a.g.hall{at}ncl.ac.uk

The MSH3 and DHFR genes, located on chromosome 5, share a common promoter but are divergently transcribed. Dysregulation of the mismatch repair pathway has been found to occur in cell line models due to co-amplification of MSH3 as a coincident effect of DHFR amplification, acquired as a mechanism generating resistance to methotrexate. The increased levels of MSH3 perturbed MutS{alpha} function resulting in hypermutability and increased resistance to thiopurines, drugs whose cytotoxic effects are triggered by MutS{alpha}. The relevance of this phenomenon in clinical samples is unknown but is extremely pertinent in childhood acute lymphoblastic leukaemia in which children are exposed for prolonged periods to both methotrexate and thiopurines such that a single amplification event involving both the DHFR and MSH3 genes may cause chemotherapeutic resistance to both agents.

Thus, we have generated a leukaemic cell line (PreB697) and a normal human lymphoblastoid cell line (TK6), which are resistant to a pharmacologically relevant dose of MTX and show that while increased DHFR levels result in methotrexate resistance, the associated increased levels of MSH3 are insufficient to perturb MutS{alpha} functionality, in terms of mismatch repair capacity or 6-thioguanine sensitivity. In addition, we show that although low level DHFR amplification occurs alone in a significant number of samples, both at disease onset and relapse, co-amplification of both MSH3 and DHFR is rarely found in primary ALL samples, even after prolonged MTX therapy and is not at a sufficiently high level to perturb MMR function.


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