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.
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Acknowledgements
This study is supported by The Sophia Foundation for Medical Research (Project number SSWO-322). We thank members of the Dutch Childhood Oncology Group (DCOG) and the German Cooperative Study Group for Childhood Acute Lymphoblastic Leukaemia (COALL) for their support of this study by collecting patient samples.
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This study is supported by The Sophia Foundation for Medical Research (Project number SSWO-322).
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Meier, M., den Boer, M., Hall, A. et al. Relation between genetic variants of the ataxia telangiectasia-mutated (ATM) gene, drug resistance, clinical outcome and predisposition to childhood T-lineage acute lymphoblastic leukaemia. Leukemia 19, 1887–1895 (2005). https://doi.org/10.1038/sj.leu.2403943
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DOI: https://doi.org/10.1038/sj.leu.2403943
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