Journal Article

DHFR and MSH3 co-amplification in childhood acute lymphoblastic leukaemia, <i>in vitro</i> and <i>in vivo</i>

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

in Carcinogenesis

Volume 28, issue 6, pages 1341-1346
Published in print June 2007 | ISSN: 0143-3334
Published online December 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgl235
DHFR and MSH3 co-amplification in childhood acute lymphoblastic leukaemia, in vitro and in vivo

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The MSH3 and dihydrofolate reductase (DHFR) genes, located on chromosome 5, share a common promoter but are divergently transcribed. Dysregulation of the mismatch repair (MMR) 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 (MTX). The increased levels of MSH3 perturbed MutSα function resulting in hypermutability and increased resistance to thiopurines, drugs whose cytotoxic effects are triggered by MutSα. The relevance of this phenomenon in clinical samples is unknown but is extremely pertinent in childhood acute lymphoblastic leukaemia (ALL) in which children are exposed for prolonged periods to both MTX and thiopurines such that a single amplification event involving both the DHFR and the 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) that are resistant to a pharmacologically relevant dose of MTX and show that while increased DHFR levels result in MTX resistance, the associated increased levels of MSH3 are insufficient to perturb MutSα functionality, in terms of MMR 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.

Journal Article.  4412 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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