title: 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.affiliation: Department of Paediatric Oncology/Haematology, Erasmus MC/Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Meier
authors.forename: M L
authors.initials: ML
authors.lastname: den Boer
authors.forename: J P P
authors.initials: JP
authors.lastname: Meijerink
authors.forename: M J C
authors.initials: MJ
authors.lastname: Broekhuis
authors.forename: M M C J
authors.initials: MM
authors.lastname: Passier
authors.forename: E R
authors.initials: ER
authors.lastname: van Wering
authors.forename: G E
authors.initials: GE
authors.lastname: Janka-Schaub
authors.forename: R
authors.initials: R
authors.lastname: Pieters
mesh_terms: D000293:Adolescent; D019070:Cell Lineage; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D016147:Genes, Tumor Suppressor; D006801:Humans; D007223:Infant; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy / Q000235:genetics*; D019656:Loss of Heterozygosity; D009687:Nuclear Proteins / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000032:analysis; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D020033:Protein Isoforms; D012333:RNA, Messenger; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins