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Cytogenetics and Molecular Genetics

Cooperative genetic defects in TLX3 rearranged pediatric T-ALL

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder, in which multiple genetic abnormalities cooperate in the malignant transformation of thymocytes. About 20% of pediatric T-ALL cases are characterized by TLX3 expression due to a cryptic translocation t(5;14)(q35;q32). Although a number of collaborating genetic events have been identified in TLX3 rearranged T-ALL patients (NOTCH1 mutations, p15/p16 deletions, NUP214-ABL1 amplifications), further elucidation of additional genetic lesions could provide a better understanding of the pathogenesis of this specific T-ALL subtype. In this study, we used array-CGH to screen TLX3 rearranged T-ALL patients for new chromosomal imbalances. Array-CGH analysis revealed five recurrent genomic deletions in TLX3 rearranged T-ALL, including del(1)(p36.31), del(5)(q35), del(13)(q14.3), del(16)(q22.1) and del(19)(p13.2). From these, the cryptic deletion, del(5)(q35), was exclusively identified in about 25% of TLX3 rearranged T-ALL cases. In addition, 19 other genetic lesions were detected once in TLX3 rearranged T-ALL cases, including a cryptic WT1 deletion and a deletion covering the FBXW7 gene, an U3-ubiquitin ligase that mediates the degradation of NOTCH1, MYC, JUN and CyclinE. This study provides a genome-wide overview of copy number changes in TLX3 rearranged T-ALL and offers great new challenges for the identification of new target genes that may play a role in the pathogenesis of T-ALL.

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Acknowledgements

PVV is financed by the Sophia Foundation for Medical Research (SSWO-440). This study was further supported by the Ter Meulen Fund, Royal Netherlands Academy of Arts and Sciences and the Foundation ‘De Drie Lichten’.

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Correspondence to J P P Meijerink.

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Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

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Van Vlierberghe, P., Homminga, I., Zuurbier, L. et al. Cooperative genetic defects in TLX3 rearranged pediatric T-ALL. Leukemia 22, 762–770 (2008). https://doi.org/10.1038/sj.leu.2405082

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