title: 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.
authors.affiliation: Department of Haematology, Cytogenetics and Molecular Genetics Laboratory, The Royal Free and University College School of Medicine, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Codrington
authors.forename: H E
authors.initials: HE
authors.lastname: O'Connor
authors.forename: G R
authors.initials: GR
authors.lastname: Jalali
authors.forename: P
authors.initials: P
authors.lastname: Carrara
authors.forename: M
authors.initials: M
authors.lastname: Papaioannou
authors.forename: S M
authors.initials: SM
authors.lastname: Hart
authors.forename: A V
authors.initials: AV
authors.lastname: Hoffbrand
authors.forename: M
authors.initials: M
authors.lastname: Potter
authors.forename: H G
authors.initials: HG
authors.lastname: Prentice
authors.forename: C J
authors.initials: CJ
authors.lastname: Harrison
authors.forename: L
authors.initials: L
authors.lastname: Foroni
mesh_terms: D000293:Adolescent; D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D006801:Humans; D015994:Incidence; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D018365:Neoplasm, Residual / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D004268:DNA-Binding Proteins; D015514:Oncogene Proteins, Fusion; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D012097:Repressor Proteins; D014157:Transcription Factors; D000097764:ETS Translocation Variant 6 Protein; C493728:RUNX1 protein, human