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

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 (DeltaTA-p73, i.e. p73Deltaex2, p73Deltaex3, p73Deltaex2/3 and DeltaN-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 DeltaTA-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 (P(trend)=0.045). Interestingly, p73Deltaex2 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 DeltaTA-p73 and relapse-risk. Our results suggest that childhood T-ALL is associated with a high expression of DeltaTA-p73. These isoforms may play a role in cellular resistance to DNA-damaging drugs in children at initial diagnosis of T-ALL.

• Authors: M Meier, M L den Boer, J P P Meijerink, M J C Broekhuis, M M C J Passier, E R van Wering, G E Janka-Schaub, R Pieters
• Journal: Leukemia (Leukemia) Vol. 20 Issue 8 Pg. 1377-84 (Aug 2006) ISSN: 0887-6924 [Print] England
• PMID: 16791269 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Nuclear Proteins
• Protein Isoforms
• RNA, Messenger
• TP73 protein, human
• Tumor Protein p73
• Tumor Suppressor Proteins

Topics

• Adolescent
• Cell Lineage
• Child
• Child, Preschool
• DNA Methylation
• DNA-Binding Proteins (genetics)
• Drug Resistance, Neoplasm
• Genes, Tumor Suppressor
• Humans
• Infant
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, genetics)
• Loss of Heterozygosity
• Nuclear Proteins (genetics)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (drug therapy, genetics)
• Protein Isoforms
• RNA, Messenger (analysis)
• Tumor Protein p73
• Tumor Suppressor Proteins