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Acute Leukemias

Differential expression of p73 isoforms in relation to drug resistance in childhood T-lineage acute lymphoblastic leukaemia

Leukemia volume 20, pages 1377–1384 (2006)Cite this article

Abstract

The T-lineage phenotype of childhood acute lymphoblastic leukaemia (ALL) is associated with an increased relapse-risk and in vitro resistance to drugs as compared to a precursor B phenotype. Antiapoptotic isoforms of p73 that lack part of the transactivation (TA) domain (ΔTA-p73, i.e. p73Δex2, p73Δex3, p73Δex2/3 and ΔN-p73) may cause resistance to anticancer agents through inhibition of p53 and/or proapoptotic p73 family members (TA-p73). We demonstrate in our study that the expression of total p73 mRNA was higher in childhood T-ALL compared to controls (P=0.004). In T-ALL, the relative contribution of antiapoptotic ΔTA-p73 (88%) was larger than of proapoptotic TA-p73 (12%). Leukaemic cells of T-ALL patients expressing higher levels of antiapoptotic p73 were more resistant to the DNA-damaging drug daunorubicin compared to cells of patients with low or negative expression or these isoforms (Ptrend=0.045). Interestingly, p73Δex2 was the most abundantly expressed antiapoptotic isoform in daunorubicin-resistant patient cells (44% of total p73). No association was found between high expression of proapoptotic TA-p73 or antiapoptotic ΔTA-p73 and relapse-risk. Our results suggest that childhood T-ALL is associated with a high expression of ΔTA-p73. These isoforms may play a role in cellular resistance to DNA-damaging drugs in children at initial diagnosis of T-ALL.

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Acknowledgements

This study is supported by The Sophia Foundation for Medical Research (project number SSWO-322). We thank Ms Aranzazu Fariña Sarasqueta for participating in this study. In addition, 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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Authors and Affiliations

  1. Department of Paediatric Oncology/Haematology, Erasmus MC/Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands

    M Meier, M L den Boer, J P P Meijerink, M J C Broekhuis, M M C J Passier & R Pieters

  2. DCOG, Dutch Childhood Oncology Group, The Hague, The Netherlands

    E R van Wering

  3. COALL, German Cooperative Study Group for Childhood Acute Lymphoblastic Leukaemia, Children's University Hospital, Hamburg, Germany

    G E Janka-Schaub

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Correspondence to M L den Boer.

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Meier, M., den Boer, M., Meijerink, J. et al. Differential expression of p73 isoforms in relation to drug resistance in childhood T-lineage acute lymphoblastic leukaemia. Leukemia 20, 1377–1384 (2006). https://doi.org/10.1038/sj.leu.2404288

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