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

Lookup NU author(s): Elizabeth Matheson, Dr Linda Hogarth, Marian Case, Professor Julie Irving, Emeritus Professor Andy Hall

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Abstract

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 coamplification of MSH3 as a coincident effect of DHFR amplification, acquired as a mechanism generating resistance to methotrexate (MTX). 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 (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 MutS alpha 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.


Publication metadata

Author(s): Hall AG; Case MC; Hogarth LA; Irving JAE; Matheson EC

Publication type: Article

Publication status: Published

Journal: Carcinogenesis

Year: 2007

Volume: 28

Issue: 6

Pages: 1341-1346

ISSN (print): 0143-3334

ISSN (electronic): 1460-2180

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/carcin/bgl235

DOI: 10.1093/carcin/bgl235

PubMed id: 17148505


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