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

Abstract

Purpose: t(12;21)(p13; q22), present in f25% 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 longterm 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 f3.5-fold lower TEL expression in t(12;21)+ compared with t(12;21)À 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)À ALL. However, AML1 expression in the leukemic cells was 2-fold higher compared with normal controls (P = 0.02). TheTEL-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.The t(12;21)(p13;q22) occurs in f25% of childhood acute lymphoblastic leukemia (ALL) and is restricted to precursor Bcell leukemia. The t(12;21) involves fusion of the TEL (ETV6) gene at 12p13 with the AML1 (CBFA2/RUNX1) gene at 21q22. The breakpoint most often occurs in intron 5 of TEL and intron 1 of AML1. A frequent translocation variant results in fusion between intron 5 of TEL and intron 2 of AML1. The TEL gene is a member of the ETS family of transcription factors and functions as a transcriptional repressor (1). AML1 encodes a transcription factor that acts as a transcription activator as well as a transcriptional repressor (2). Both genes are frequent targets of chromosomal translocations in a variety of myeloid and lymphoid leukemias (3, 4).Since the discovery of t(12;21), several studies addressed the prognostic value of this particular translocation (reviewed by Loh and Lubnitz; ref. 5). In general, t(12;21)-positive ALL is associated with a favorable prognosis although conflicting results have been reported (5). In the Dutch Childhood Oncology Group ALL-7 and ALL-8 treatment ...

ETV6/RUNX1-positive relapses evolve from an ancestral clone and frequently acquire deletions of genes implicated in glucocorticoid signaling

“…These properties concur with similar earlier observations, which also demonstrated that, although both clones derive from the same source, some of their genetic features might, nevertheless, differ completely. 14,16,19 Taking into account that, even in cases without a deletion the nonrearranged ETV6 gene is generally not expressed, 43,44 it appears likely that ETV6 inactivation is a critical step in the pathogenesis of E/R-positive leukemia.…”

Anemia and survival in childhood acute lymphoblastic leukemia

“…Several studies have analyzed the clinical and biological features in ALL patients carrying the translocation t(12;21) leading to the TEL-AML1 gene fusion. [27][28][29][30][31][32][33][34][35][36][37][38] None of those studies reported a low Hb level to be associated with TEL-AML1. One study addressed this issue, but failed to demonstrate a correlation between Hb and TEL-AML1, probably due to the limited number of patients analyzed (11/51 patients TEL-AML1 + ).…”

Reduced PDEF Expression Increases Invasion and Expression of Mesenchymal Genes in Prostate Cancer Cells

“…Chromosomal translocations of multiple Ets family members are frequent in various cancer types, including FLI-1 (3,4), ERG (3,5), ETV1 (6), ETV4 (7), and FEV, in Ewing's sarcomas and TEL/ETV6 in different types of leukemia, fibrosarcoma, lymphoma, and myelodysplastic syndrome (8)(9)(10), indicating a critical role for Ets factors in tumorigenesis. Furthermore, deregulated activity of Ets factors is observed in many cancers and apparently contributes not only to tumorigenesis but also to tumor progression, outcome, angiogenesis, epithelial-to-mesenchymal transition (EMT), and metastasis (11).…”