Differential expression of p73 isoforms in relation to drug resistance in childhood T-lineage acute lymphoblastic leukaemia
Leukemia , Volume 20 - Issue 8 p. 1377- 1384
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, p73Δex2Δ3 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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|Organisation||Department of Pediatrics|
Meier, M, den Boer, M.L, Meijerink, J.P.P, Broekhuis, M.J.C, Passier, M.M, van Wering, E.R, … Pieters, R. (2006). Differential expression of p73 isoforms in relation to drug resistance in childhood T-lineage acute lymphoblastic leukaemia. Leukemia, 20(8), 1377–1384. doi:10.1038/sj.leu.2404288