Natural history of childhood leukaemia

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• Mel Greaves, Institute of Cancer Research, Sutton
• Friday 22 October 2010, 16:30-17:30
• Cancer Research UK Cambridge Research Institute, Lecture Theatre.

If you have a question about this talk, please contact Katrien Van Look.

Cancer clone expansion is a Darwinian, evolutionary process of genetic diversification and selection – in somatic cells inhabiting a tissue ecosystem. Childhood acute lymphoblastic leukaemia (ALL), though an intrinsically lethal malignancy, develops over a short time frame and has only modest genetic complexity. It is therefore amenable to interrogation of its pre-clinical evolutionary or natural history, i.e. the timing and sequence of critical mutational events and, ultimately, the causal basis of this process.

For the common variant, B cell precursor ALL , we have determined the temporal sequence of mutations. ETV6 -RUNX1 fusion (and hyperdiploidy) are commonly pre-natal and presumed initiating events followed by a modest set of secondary copy number alterations (CNA) or sequence-based mutations more proximal to diagnosis. Current whole genome sequencing screens should provide a complete audit of ‘driver’ mutations for ALL . Genetic studies on monozygotic twins with concordant and discordant ALL have been invaluable in these studies as has been modelling studies with murine and human cells.

Single cell analysis with multiplexed probes for ETV6 -RUNX1 fusion gene and CNA have enabled us to investigate the detailed genetic architecture of clones in ALL . This reveals that the evolutionary trajectory of this cancer (and we believe most others) is non-linear, and with a branching sub-clonal architecture of genetically distinct sub-clones, as anticipated on Darwinian principles. We have extended this analysis to show that the ‘stem’ or propagating cells driving this process are themselves genetically diverse or variegated in individual patients. Current pan-genomic snapshots (SNP arrays or sequencing) of ALL and other cancer cells are largely blind to this underlying heterogeneity. These differing perspectives of genetic architecture in cancer are of some clinical consequence.

These data have also provided a time-ordered framework for considering the genetic (inherited) and exposure components of the aetiological pathway in ALL . This has led to the identification of several inherited gene variants that confer susceptibility and endorsed the idea that the immune response to common infection(s) is a likely promotional trigger.

Selected references:

Greaves MF, Maia AT, Wiemels JL, Ford AM (2003) Leukemia in twins: lessons in natural history. Blood, 102: 2321-2333.

Greaves MF, Wiemels J (2003) Origins of chromosome translocations in childhood leukaemia. Nature Rev Cancer, 3: 639-649.

Greaves M (2006) Infection, immune responses and the aetiology of childhood leukaemia. Nat Rev Cancer, 6: 193-203.

Hong D, Gupta R, Ancliff P, Atzberger A, Brown J, Soneji S, Green J, Colman S, Piacibello W, Buckle V, Tsuzuki S, Greaves M, Enver T (2008) Initiating and cancer-propagating cells in TEL -AML1-associated childhood leukemia. Science, 319: 336-339.

Ford AM, Palmi C, Bueno C, Hong D, Cardus P, Knight D, Cazzaniga G, Enver T, Greaves M (2009) The TEL -AML1 leukemia fusion gene dysregulates the TGF  pathway in early B lineage progenitor cells. J Clin Invest, 119: 826-836.

Papaemmanuil E, Hosking FJ, Vijayakrishnan J, Price A, Olver B, Sheridan E, Kinsey SE, Lightfoot T, Roman E, Irving JAE , Allan JM, Tomlinson IP, Taylor M, Greaves M, Houlston RS (2009) Loci on 7p12.2, 10q21.2 and 14q11.2 are associated with risk of childhood acute lymphoblastic leukemia. Nature Genet, 41: 1006-1010.

Bateman CM, Colman SM, Chaplin T, Young BD, Eden TO, Bhakta M, Gratias EJ, van Wering ER, Cazzaniga G, Harrison CJ, Hain R, Ancliff P, Ford AM, Kearney L, Greaves M (2010) Acquisition of genome-wide copy number alterations in monozygotic twins with acute lymphoblastic leukemia. Blood, 115: 3553-3558.

Greaves M (2010) Cancer stem cells: back to Darwin? Sem Cancer Biol, 20: 65-70.

Anderson K, Lutz C, van Delft FW, Bateman CM, Guo Y, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature, in press.

This talk is part of the Cambridge Cancer Centre seminars series.

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