Analysis of ETV6/AML1 abnormalities in acute lymphoblastic leukaemia: incidence, alternative spliced forms and minimal residual disease value

Abstract

The t(12;21)(p13;q22) translocation, resulting in the fusion of the ETV6 and AML1 genes, occurs in 20-25% of paediatric B-lineage acute lymphoblastic leukaemias (ALL). The identification of the fusion product has important prognostic and therapeutic implications as the translocation has been associated with a favourable clinical outcome. The aim of this study was threefold: (i) to assess the frequency and clinical association of the fusion gene in patients with and without a cytogenetically detectable chromosome 12 and/or 21 abnormality or failed cytogenetic results, (ii) to characterize alternative forms of ETV6/AML1 transcripts, and (iii) to use ETV6/AML1 as a molecular marker for the investigation of minimal residual disease (MRD). ETV6/AML1 fusion was detected in 22 (39%) of 56 cases studied by reverse transcriptase polymerase chain reaction (RT-PCR). ETV6/AML1 fusion was found in nine out of 16 (56%) cases with a cytogenetically visible chromosome 12 abnormality, but also in nine out of 29 patients (31%) without a chromosome 12 abnormality or patients with failed cytogenetics (four out of 11 patients, 36%), making this the most common cytogenetic abnormality in childhood ALL. Alternatively spliced ETV6/AML1 forms were investigated in 14 of the positive patients. Exon 5 of ETV6 was fused in frame to all AML1 exons, except exon 4. Fusion to exon 6 of AML1 resulted in one amino acid change. The presence of ETV6/AML1 was associated with a lower white blood cell count (Student's t-test; P = 0.009) and common (c)ALL phenotype (chi(2) test; P > 0.001), but no better disease-free survival. Our study shows that (i) RT-PCR is the most effective approach for the detection of t(12;21) in childhood ALL, (ii) the association of ETV6/AML1 and chromosome 12 and/or 21, seen in 56% of our cases, further confirms existing data, (iii) overall survival of patients with t(12;21) was not better than other cytogenetics groups, and (d) MRD analysis using ETV6/AML1 fusion is specific, but not sensitive enough to avoid false negative results.

Prevalence of Gene Rearrangements in Mexican Children with Acute Lymphoblastic Leukemia: A Population Study—Report from the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia

“…In India [ 14 ] and Brazil [ 15 ], reported frequencies were 7% and 11.3%, respectively ( Table 2 ). However, we observed a lower frequency of the ETV6-RUNX1 rearrangement in comparison to reports from developed countries [ 11 – 13 , 20 ]. Interestingly, the disparities regarding gene rearrangement prevalence among countries could be explained by environmental factors as playing an important role in the development of childhood leukemia, as would be the case of Mexico [ 1 , 6 ].…”

Clinical features of the most common fusion genes in childhood acute lymphoblastic leukemia

“…The frequency of patients with the TEL/AML1 fusion gene was 17.1%, demonstrating that this is the most common genetic defect in Serbian children with ALL, as in many other populations [18,19]. Biological and clinical characteristics and therapy response of TEL/AML1 positive patients were also similar to other reports [20].…”

Persistence of TEL‐AML1 transcript in acute lymphoblastic leukemia in long‐term remission

“…The investigation of minimal residual disease (MRD) using TEL‐AML1 transcript as a marker has been carried out on a limited number of patients to date. Although it is a minor examination, the relation between relapse and the persistence of detectable MRD shows heterogeneity 4,11,12 . A long follow‐up period to determine the prognostic significance of TEL‐AML1 fusion, and to clarify whether the persistence of the TEL‐AML1 transcript truly correlates with recurrence of ALL is required.…”