Prenatal origin of acute lymphoblastic leukaemia in children

Background There is little current insight into the natural history of chil dhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently-seen in the common fo rm of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally. Methods We identified, by reverse-transcriptase PCR screening of blood or b one marrow, TEL-AML1 fusion in 12 children, plus a pair of identical twins, aged 2-5 years from Italy and the UK, who had newly diagnosed acute lympho blastic leukaemia. We amplified and sequenced the genomic TEL-AMLI fusion g ene with a long-distance inverse PCR method. Primers were designed that cou ld be used in short-range PCR to screen for patient-specific, leukaemia clo ne-specific TEL-AMLI genomic fusion sequences in neonatal blood spots from each child. Findings We initially identified TEL-AMLI fusion sequences in blood spots f rom the identical twins, diagnosed with concordant acute lymphoblastic leuk aemia at age 4 years, who shared a single or clonotypic TEL-AMLI sequence t hat suggested prenatal origin in one twin. Three children were excluded bec ause control genes could not be amplified. Of the other nine patients, six had positive blood spots. Blood spots that were classified as negative were uninformative. Interpretation Our findings showed that childhood acute lymphoblastic leuka emia is frequently initiated by a chromosome translocation event in utero. Studies in identical twins show however that such an event is insufficient for clinical leukaemia and that a postnatal promotional event is also requi red.