The fetal origins of childhood leukaemia

There is now compelling evidence that chromosome translocations are often the first or initiating events in leukaemia, occurring prenatally during fetal development. This evidence comes from two sources: identical twin infants or children with concordant acute lymphoblastic leukaemia and retrospective scrutiny of neonatal blood spots.
The most common structural genetic abnormality in childhood leukaemia is a fusion of two genes, TEL and AML1. This is generated by a chromosome translocation between chromosomes 12 and 21. Simultaneous breaks in the TEL gene (chromosome 12) and AML1 gene (chromosome 21) are followed by errorprone repair that stitches up the DNA across chromosomes 12 and 21, joining the normally separate TEL and AML1 genes together to form a chimeric or fusion gene. As in other chromosomal translocations, the DNA breaks always occur in non coding regions (introns) of genes. The precise breakpoints in the TEL and AML1 genes can be iden tified or mapped by the "long distance" polymerase chain reaction (PCR). Breaks always occur, more or less randomly, within a limited region of these genes, but each patient's leukaemic cells have a unique (or clone specific) breakpoint in the DNA sequence.
Analysis of pairs of identical twins with concordant acute lymphoblastic leukaemia shows that leukaemic cells from both twins in a pair share the identical breakpoints in TEL and AML1 genes or, in the case of infant twins with acute lymphoblastic leukaemia, the same breakpoints in the MLL gene. Monozygotic twins are, of course, themselves monoclonal and genetically identical, but gene breakpoints in leukaemic cells are not inherited-they disappear in remission.
The only plausible explanation for twin leukaemias sharing the same gene breakpoints is that the chromosomal breaks generating the fusion gene must have occurred just once, in one blood stem cell, in one twin in utero. Subsequently, but still in utero, descendent progeny of this transformed cell spread to the other twin, presumably via the anastomoses that exist within shared, single (monochorionic) placentas. We assume that at this early stage a clinically silent or covert preleukaemic clone is generated which, after birth, may evolve to full blown leukaemia anything from two months to 14 years later.
Further evidence that childhood leukaemia can originate before birth comes from scrutiny of neonatal blood spots or Guthrie cards. PCR tests for specific fusion genes, designed for each patient, can detect as few as 1 20 leukaemic cells in a blood spot.

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