Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1- TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia.
PURPOSE: t(12;21)(p13; q22), present in approximately 25% of pediatric precursor B-ALL, is highly sensitivity to L-asparaginase and the prognosis depends on the intensity of the treatment protocol. This study analyzes the relationship between the mRNA expression of the genes and fusion products involved in t(12;21), in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, and long-term clinical outcome in t(12;21)+ acute lymphoblastic leukemia (ALL) patients. EXPERIMENTAL DESIGN: Long-term clinical outcome in 45 t(12;21)+ ALL patients was related to mRNA expression of TEL, AML1, TEL-AML1, and AML1-TEL, determined by real-time quantitative PCR, and the in vitro sensitivity to prednisolone, vincristine, and L-asparaginase, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. RESULTS: A significant approximately 3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)- ALL samples (P = 0.006) and normal controls (P = 0.004) was found. Expression of AML1 did not differ between t(12;21)+ and t(12;21)- ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). The TEL-AML1 fusion product was expressed in all t(12;21)+ cases, whereas the reciprocal fusion product AML1-TEL was expressed in only 76%. High expression levels of TEL-AML1 [hazard ratio (HR), 1.3; 95% confidence interval (95% CI), 1.10-1.57; P = 0.003], AML1-TEL (HR, 4.9; 95% CI, 1.99-12.40; P = 0.001) and AML1 (HR, 1.1; 95% CI, 1.03-1.22; P = 0.006) were associated with a poor long-term clinical outcome within t(12;21)+ ALL. Cellular drug resistance towards prednisolone, vincristine, and L-asparaginase could not explain this predictive value. Multivariate analysis including age and WBC showed that only high AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL. CONCLUSION: High AML1-TEL expression is an independent poor prognostic factor in t(12;21)+ childhood ALL.
|Keywords||*Gene Expression Regulation, Neoplastic, *Translocation, Genetic, Asparaginase/pharmacology, Cell Survival/drug effects, Child, Chromosomes, Human, Pair 12/*genetics, Chromosomes, Human, Pair 21/*genetics, Core Binding Factor Alpha 2 Subunit, DNA-Binding Proteins/genetics, Disease-Free Survival, Humans, In Situ Hybridization, Fluorescence, Nuclear Proteins/genetics, Oncogene Proteins, Fusion/genetics, Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics/*pathology, Prednisolone/pharmacology, Proto-Oncogene Proteins c-ets, Proto-Oncogene Proteins/genetics, RNA, Messenger/genetics/metabolism, Repressor Proteins/genetics, Reverse Transcriptase Polymerase Chain Reaction, Transcription Factors/genetics, Treatment Outcome, Vincristine/pharmacology|
|Persistent URL||dx.doi.org/10.1158/1078-0432.CCR-04-1829, hdl.handle.net/1765/13784|
Stams, W.A., den Boer, M.L., Beverloo, H.B., Meijerink, J.P.P., van Wering, E.R., Janka-Schaub, G.E., & Pieters, R.. (2005). Expression levels of TEL, AML1, and the fusion products TEL-AML1 and AML1- TEL versus drug sensitivity and clinical outcome in t(12;21)-positive pediatric acute lymphoblastic leukemia.. Clinical Cancer Research, 11(8), 2974–2980. doi:10.1158/1078-0432.CCR-04-1829