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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

Authors' Affiliations: ¹ Division of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital; ² Department of Clinical Genetics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; ³ Dutch Childhood Oncology Group, the Hague, the Netherlands; and ⁴ Childhood Acute Lymphoblastic Leukemia study group, Hamburg, Germany

Requests for reprints: Wendy A.G. Stams, Division of Pediatric Oncology/Hematology, Erasmus MC, Sophia Children's Hospital, Dr. Molewaterplein 60, 3015 GJ Rotterdam, the Netherlands. Phone: 0031-10-4089379; Fax: 0031-10-4089433; E-mail: m.l.denboer{at}erasmusmc.nl.

Purpose: t(12;21)(p13; q22), present in 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 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.

Key Words: TEL-AML1 • prognosis • additional genetic changes • AML1-TEL

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