Leukaemia, a diverse disease with variable clinical outcomes
- By:Wayne Channon
It has long been recognised that childhood leukaemia is not one homogeneous disease. The major morphological division into acute lymphoblastic leukaemia and acute myeloblastic leukaemia is supplemented by the identification of a range of subsets based on gene expression, antigens that delineate cell type or differentiation status and chromosomal and molecular abnormalities. These include chromosome translocations and changes in chromosome number. At a more subtle level, there may also be gene deletions or single nucleotide base changes in genes.
This molecular archaeology has uncovered what has long been suspected; the acute leukaemias are biologically diverse diseases. Moreover, in acute lymphoblastic leukaemia these subgroups segregate with age, which may help explain the considerable difference in outcome between infants aged less than one year, children between two and ten years old, and adults. A similar spectrum of molecular diversity exists for acute myeloblastic leukaemia. Several of these molecular abnormalties have independent prognostic importance in the context of particular treatment regimens.
What most descriptions of leukaemic stem cells obscure, however is the dynamic, evolving nature of the disease, a feature it shares with all other cancers. Leukaemia is a clonal disease originating in a single stem cell and evolves by the accrual of mutations within a clone.
There is now compelling evidence that chromosome translocations are often the first or initiating events in leukaemia, occurring prenatally during foetal development. This evidence comes from two sources. The most common structural genetic abnormality in childhood leukaemia is a fusion of two genes. 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 error-prone 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.
Analysis of pairs of identical twins with concordant acute lymphoblastic leukaemia shows that leukaemic stem cells from leukaemic cells from bot 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 stem cells are not inherited.
About the author:
Wayne Channon, Director of Cells4Life Ltd, a stem cells and cord blood bank t. They specialize in umbilical cord blood collection .