Initially complex, always heterogeneous

Darren J. Burgess

The genetic complexity and heterogeneity of cancer is becoming increasingly appreciated through genomic and histological analyses. Two recent studies add further weight to this concept, revealing that even the subpopulation of leukaemia-initiating cells in individual patient samples can have surprising genetic heterogeneity.

By analysing individual leukaemic cells in each sample population, researchers found that the leukaemia initiating cell subpopulation (defined by cell surface markers or by serial xenotransplantation in mice)maintained a genetic heterogeneity that was similar to the population of leukaemia cells in the sample. This suggests that the linear clonal succession model of cancer evolution, in which cancers progress through single-cell clone bottlenecks, might be an oversimplification. The genetic heterogeneity and the branching evolutionary trajectories evident in the samples evoke a remarkably Darwinian perspective of the evolution of leukaemia-initiating cells.

Interestingly, a comparison of multiple leukaemia samples from individual patients during disease progression and post-treatment relapse revealed that shifts can occur in the dominance of the subclones, although the subclonal diversity is generally maintained.

It will be interesting to see whether these diverse subclones of cancerinitiating
cells equally fulfil all the biological properties of cancer stem cells. Another key question is whether the extent of genetic complexity seen for ALL-initiating cells will be mirrored in other cancers, given that acute leukaemias have a greater proportion of cancer-initiating cells compared with some solid tumours.

Finally, this genetic heterogeneity suggests that the therapeutic targeting of cancer-initiating cells will be a considerable challenge. However, the ability to isolate and study rare subclones in xenografts opens a pathway to developing therapies that would target all subclones.

See more:
Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469,356–361 (2011).

Notta, F. et al. Evolution of human BCR–ABL1 lymphoblastic leukaemia-initiating cells. Nature 469, 362–367 (2011).