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Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome

Abstract

Clinical heterogeneity within t(12;21) or TEL/AML1-positive ALL (25% of childhood common/preB ALL) indicates that additional genetic changes might contribute to outcome. We studied the relation between additional genetic changes in TEL(ETV6) and AML1(RUNX1) (FISH), drug sensitivity (MTT assay) and clinical outcome in 143 DCOG and COALL-treated t(12;21)-positive ALL patients. Additional genetic changes in TEL and AML1 were present in 83% of the patients, and consisted of (partial) deletion of the second TEL gene (70%), an extra AML1 gene (23%) or an extra der(21)t(12;21) (10%). More than one additional change was observed in 20%. Disease-free survival (pDFS) of DCOG patients without additional genetic changes (4 years pDFS±s.e. 53±17%) and of those with an extra der(21)t(12;21) (60±22%) is poorer than that of compared to patients with other additional genetic changes in TEL or AML1 (79±6%; P-trend=0.02). This was mainly due to the occurrence of early relapses within 2.5 years after the first diagnosis. Similar observations were found in the COALL cohort, albeit not significant owing to limited follow-up. Multivariate analysis including age, WBC and genetic abnormalities in TEL and/or AML1 showed that especially, in vitro resistance to prednisolone (hazard ratio 5.78, 95% CI 1.45–23.0; P=0.01) is an independent prognostic factor in DCOG- and COALL-treated t(12;21)-positive ALL.

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Acknowledgements

We wish to express our gratitude to the members of the DCOG and the German COALL study group for their support to this study by providing leukemic samples. This study was financially supported by Grants from the Sophia Foundation for Medical Research (SSWO Grant 309) and the Pediatric Oncology Foundation Rotterdam, The Netherlands.

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Correspondence to M L den Boer.

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Stams, W., Beverloo, H., den Boer, M. et al. Incidence of additional genetic changes in the TEL and AML1 genes in DCOG and COALL-treated t(12;21)-positive pediatric ALL, and their relation with drug sensitivity and clinical outcome. Leukemia 20, 410–416 (2006). https://doi.org/10.1038/sj.leu.2404083

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