Prenatal origin of acute lymphoblastic leukaemia in children.
BACKGROUND
There is little current insight into the natural history of childhood leukaemia or the timing of relevant mutational events. TEL-AML1 gene fusion due to chromosomal translocation is frequently seen in the common form of childhood acute lymphoblastic leukaemia. We investigated whether this abnormality arises prenatally.


METHODS
We identified, by reverse-transcriptase PCR screening of blood or bone 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 lymphoblastic leukaemia. We amplified and sequenced the genomic TEL-AML1 fusion gene with a long-distance inverse PCR method. Primers were designed that could be used in short-range PCR to screen for patient-specific, leukaemia clone-specific TEL-AML1 genomic fusion sequences in neonatal blood spots from each child.


RESULTS
We initially identified TEL-AML1 fusion sequences in blood spots from the identical twins, diagnosed with concordant acute lymphoblastic leukaemia at age 4 years, who shared a single or clonotypic TEL-AML1 sequence that suggested prenatal origin in one twin. Three children were excluded because 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.


CONCLUSIONS
Our findings showed that childhood acute lymphoblastic leukaemia 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 required.
Wiemels
J L
JL
Leukaemia Research Fund Centre, Institute of Cancer Research, Chester Beatty Laboratories, London, UK.
Cazzaniga
G
G
Daniotti
M
M
Eden
O B
OB
Addison
G M
GM
Masera
G
G
Saha
V
V
Biondi
A
A
Greaves
M F
MF
D002051:Burkitt Lymphoma / Q000196:embryology* / Q000235:genetics*; D002675:Child, Preschool; D050676:Core Binding Factor Alpha 2 Subunit; D004200:Diseases in Twins / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009363:Neoplasm Proteins / Q000097:blood* / Q000235:genetics; D015514:Oncogene Proteins, Fusion; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014178:Translocation, Genetic / Q000235:genetics*; D000097764:ETS Translocation Variant 6 Protein
D050676:Core Binding Factor Alpha 2 Subunit; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; C102421:TEL-AML1 fusion protein; D000097764:ETS Translocation Variant 6 Protein