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Relation between genetic variants of the ataxia telangiectasia-mutated (ATM) gene, drug resistance, clinical outcome and predisposition to childhood T-lineage acute lymphoblastic leukaemia

Lookup NU author(s): Emeritus Professor Andy Hall, Professor Julie Irving, Lynne Minto

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Abstract

The T-lineage phenotype in children with acute lymphoblastic leukaemia (ALL) is associated with in vitro drug resistance and a higher relapse-risk compared to a precursor B phenotype. Our study was aimed to investigate whether mutations in the ATM gene occur in childhood T-lineage acute lymphoblastic leukaemia (T-ALL) that are linked to drug resistance and clinical outcome. In all, 20 different single nucleotide substitutions were found in 16 exons of ATM in 62/103 (60%) T-ALL children and 51/99 (52%, P = 0.21) controls. Besides the well-known polymorphism D1853N, five other alterations (S707P, F858L, P1054R, L1472W, Y1475C) in the coding part of ATM were found. These five coding alterations seem to occur more frequently in T-ALL (13%) than controls (5%, P = 0.06), but did not associate with altered expression levels of ATM or in vitro resistance to daunorubicin. However, T-ALL patients carrying these five coding alterations presented with a higher white blood cell count at diagnosis (P = 0.05) and show an increased relapse-risk (5-year probability of disease-free survival (pDFS) = 48%) compared to patients with other alterations or wild-type ATM (5-year pDFS = 76%, P = 0.05). The association between five coding ATM alterations in T-ALL, their germline presence, white blood cell count and unfavourable outcome may point to a role for ATM in the development of T-ALL in these children. © 2005 Nature Publishing Group. All rights reserved.


Publication metadata

Author(s): Meier, M., den Boer, M., Hall, A.G., Irving, J.A.E., Passier, M., Minto, C.L.J., van Wering, E., Janka-Schaub, G., Pieters, R.

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2005

Volume: 19

Issue: 11

Pages: 1887-1895

Print publication date: 01/11/2005

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

URL: http://dx.doi.org/10.1038/sj.leu.2403943

DOI: 10.1038/sj.leu.2403943

PubMed id: 16167060


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