Role of the TEL-AML1 fusion gene in the molecular pathogenesis of childhood acute lymphoblastic leukaemia

Abstract

Balanced chromosomal translocations are frequently associated with haematopoietic neoplasms and often involve genes that encode transcription factors, which play critical roles in normal haematopoiesis. Fusion oncoproteins that arise from chimeric genes generated by such translocations are usually stable and consistent molecular markers for a given disease subtype and contribute to the leukaemogenic processes. The t(12;21)(p13;q22) chromosomal translocation is the most frequent illegitimate gene recombination in paediatric cancer, occurring in approximately 25% of common (c) B-cell precursor acute lymphoblastic leukaemia (cALL) cases. The rearrangement results in the in-frame fusion of the 5 0 region of the ETS-related gene, TEL (ETV6), to almost the entire AML1 (RUNX1) locus and is associated with favourable prognosis following conventional therapeutic strategies. We discuss here the prenatal origins of the TEL/AML1 translocation as an initiating mutation, the role of TEL-AML1 in cellular transformation and the molecular mechanisms by which the chimeric protein imposes altered patterns of gene expression.

Molecular Genetic Studies on 167 Pediatric ALL Patients from Different Areas of Pakistan Confirm a Low Frequency of the Favorable Prognosis Fusion Oncogene TEL-AML1 (t 12; 21) in Underdeveloped Countries of the Region

“…Seventeen out of 167 (10.2%) samples were found to be positive for TEL-AML1, which is lower than the frequencies reported from developed countries (Zelent et al, 2004). Previously, the prevalence of TEL-AML1 fusion oncogene in Pakistani population has been reported by to be 11% (Iqbal and Tanveer, 2006) which is in accordance with our findings, although that study lacked clinical outcome of TEL-AML1 positive patients.…”

“…Molecular diagnosis of t (12; 21)-positive ALL may identify a subgroup of patients which do not require intensive treatment for cure. TEL-AML1 fusion is reported to be 20-25% in childhood ALL (Shaker et al, 2001;Zelent et al, 2004;Coppola, 2010). Majority of patients display a precursor B-cell immunophenotype, low WBC count, and good response to treatment (Zaza et al, 2004;Riccio et al, 2010).…”

“…Majority of patients display a precursor B-cell immunophenotype, low WBC count, and good response to treatment (Zaza et al, 2004;Riccio et al, 2010). However, most of the comprehensive studies related to TEL-AML1 frequency are from Europe and US (Shaker et al, 2001;Zelent et al, 2004;Coppola, 2010). Due to its prognostic significance and implication in drug selection, a detailed account of TEL-AML1 frequency among childhood ALL is required for proper treatment strategies in a given population.…”

Dimer-tetramer transition controls RUNX1/ETO leukemogenic activity

“…This hypothesis is reinforced by the observations made with RUNX1 dimers formed by 2 parallel oriented RUNX1 helices, as it exists in the fusion protein TEL/ RUNX1. 43 In addition, the replacement of the NHR2 domain in RUNX1/ETO with 4 tandem repeats of a self-oligomerizing mutant HOT SPOTS OF RUNX1/ETO DIMER-TETRAMER TRANSITION 611 BLOOD, 29 JULY 2010 ⅐ VOLUME 116, NUMBER 4For personal use only. on March 25, 2019. by guest www.bloodjournal.org From of FKBP results in homo-oligomers with the ability to bind DNA with similar affinity as RUNX1/ETO (data not shown) and to enhance the clonogenic potential of primary murine bone marrow cells.…”

Current Role of Genetics in Hematologic Malignancies

“…It is seen in approximately 25 % cases. This translocation results in the fusion of the 5 0 region of the gene TEL (ETV6), to the AML1 (RUNX1) locus and is associated with favorable prognosis [23]. Apart from providing important prognostic information certain genetic aberrations have emerged as predictive markers.…”