Complexity of clonal architecture in childhood leukaemia: Darwin re-visited


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Mel Greaves
The Institute of Cancer Research, Royal Marsden Hospital, Sutton, UK

Abstract

<p>Mutation-driven cancer clone expansion has long been regarded as a Darwinian process of somatic cell evolution. The prevailing imagery has been of a linear succession of clones, coupled with progressive acquisition of independent mutations and paralleled, for epithelial carcinomas, with a histopathological ecology of tissue disruption. There is however increasing evidence that this view is too simplistic and disguises more complex, non-linear dynamics, as in evolution in general. Leukaemias offer a tractable approach to this problem in so far as they develop over a shorter time frame and generally have less complex genetics and minimal genetic instability. On the other hand, by the time an acute leukaemia is diagnosed, its evolutionary trajectory is history.</p><p>We were able to backtrack the previously covert natural, evolutionary history of childhood acute lymphoblastic leukaemia (ALL) using (a) archived neonatal blood spots from patients; (b) comparative genomics of leukaemias from identical twin pairs with leukaemia; and (c) modelling with murine and human stem cells.</p><p>These data reveal a common sequence of developmentally timed events involving pre-natal initiation by fusion gene formation (or hyperdiploidy) followed by post-natal acquisition of multiple copy number alterations (mostly deletions) and occasional sequence mutations. This picture has the appearance of a linear succession but mutations screens, either specific or genome-wide, generally disguise clonal architecture. We used multi (3/4) colour gene probes to explore the genetic complexity of ALL initiated by ETV6-RUNX1 at the single cell level. Most cases were remarkably complex in their clonal, genetic architecture with multiple distinctive subclones. The picture of clonal evolution or architecture so revealed is very much more like Darwin’s original branching tree structure than a simple linear progression.</p><p>There are several challenging implications of these findings including the potential clonal origins of progression and relapse and the likely multiplicity of stem cells – contrary to the more simplistic, unitary models.</p><br>