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SUMMARY:Natural history of childhood leukaemia - Mel Greaves\, Institute o
 f Cancer Research\, Sutton
DTSTART:20101022T153000Z
DTEND:20101022T163000Z
UID:TALK27087@talks.cam.ac.uk
CONTACT:Katrien Van Look
DESCRIPTION:Cancer clone expansion is a Darwinian\, evolutionary process o
 f 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 interroga
 tion 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.\n\nFor 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 seq
 uence-based mutations more proximal to diagnosis.  Current whole genome se
 quencing screens should provide a complete audit of ‘driver’ mutations
  for ALL.  Genetic studies on monozygotic twins with concordant and discor
 dant ALL have been invaluable in these studies as has been modelling studi
 es with murine and human cells.\n\nSingle cell analysis with multiplexed p
 robes for ETV6-RUNX1 fusion gene and CNA have enabled us to investigate th
 e detailed genetic architecture of clones in ALL.  This reveals that the e
 volutionary trajectory of this cancer (and we believe most others) is non-
 linear\, and with a branching sub-clonal architecture of genetically disti
 nct sub-clones\, as anticipated on Darwinian principles.  We have extended
  this analysis to show that the ‘stem’ or propagating cells driving th
 is 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 s
 ome clinical consequence.\n\nThese 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 t
 he idea that the immune response to common infection(s) is a likely promot
 ional trigger.\n\nSelected references:\n\nGreaves MF\, Maia AT\, Wiemels J
 L\, Ford AM (2003)  Leukemia in twins: lessons in natural history.  Blood\
 , 102: 2321-2333.\n\nGreaves MF\, Wiemels J (2003)  Origins of chromosome 
 translocations in childhood leukaemia.  Nature Rev Cancer\, 3: 639-649.\n\
 nGreaves M (2006)  Infection\, immune responses and the aetiology of child
 hood leukaemia.  Nat Rev Cancer\, 6: 193-203.\n\nHong D\, Gupta R\, Anclif
 f P\, Atzberger A\, Brown J\, Soneji S\, Green J\, Colman S\, Piacibello W
 \, Buckle V\, Tsuzuki S\, Greaves M\, Enver T (2008)  Initiating and cance
 r-propagating cells in TEL-AML1-associated childhood leukemia.  Science\, 
 319: 336-339.\n\nFord 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.\n\nPapaemmanuil E\, Hosking FJ\, Vijayakri
 shnan J\, Price A\, Olver B\, Sheridan E\, Kinsey SE\, Lightfoot T\, Roman
  E\, Irving JAE\, Allan JM\, Tomlinson IP\, Taylor M\, Greaves M\, Houlsto
 n 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.
 \n\nBateman CM\, Colman SM\, Chaplin T\, Young BD\, Eden TO\, Bhakta M\, G
 ratias 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.\n\nGreaves M (2010)  Cancer stem cells: back to
  Darwin?  Sem Cancer Biol\, 20: 65-70.\n\nAnderson 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 clo
 nal architecture and propagating cells in leukaemia.  Nature\, in press.\n
LOCATION:Cancer Research UK Cambridge Research Institute\, Lecture Theatre
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