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Analysis of ETV6/AML1 abnormalities in acute lymphoblastic leukaemia: incidence, alternative spliced forms and minimal residual disease value
Author(s) -
Codrington Rosalind,
O'connor Helen E.,
Jalali G. Reza,
Carrara Paola,
Papaioannou Mary,
Hart Stephen M.,
Hoffbrand A. Victor,
Potter Michael,
Prentice H. Grant,
Harrison Christine J.,
Foroni Letizia
Publication year - 2000
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2000.02464.x
Subject(s) - etv6 , minimal residual disease , chromosomal translocation , fusion transcript , fusion gene , biology , exon , microbiology and biotechnology , cancer research , medicine , immunology , genetics , gene , bone marrow
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 (χ 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.