The role of the RAS pathway in iAMP21-ALL

  1. Lookup NU author(s)
  2. Dr Sarra Ryan
  3. Elizabeth Matheson
  4. Dr Paul Sinclair
  5. Dr Matthew Bashton
  6. Claire Schwab
  7. Dr Matthew Partington
  8. Alannah Elliott
  9. Lynne Minto
  10. Stacey Richardson
  11. Dr Thahira Rahman
  12. Professor Bernard Keavney
  13. Professor Roderick Skinner
  14. Dr Nicholas Bown
  15. Dr Mauro Santibanez Koref
  16. Professor Anthony Moorman
  17. Professor Julie Irving
  18. Professor Christine Harrison
Author(s)Ryan SL, Matheson E, Grossmann V, Sinclair P, Bashton M, Schwab C, Towers W, Partington M, Elliott A, Minto L, Richardson S, Rahman T, Keavney B, Skinner R, Bown N, Haferlach T, Vandenberghe P, Haferlach C, Santibanez-Koref M, Moorman AV, Kohlmann A, Irving JA, Harrison CJ
Publication type Article
JournalLeukemia
Year2016
Volume
IssueePub ahead of Print
Pages
ISSN (print)0887-6924
ISSN (electronic)1476-5551
Full text is available for this publication:
Intrachromosomal amplification of chromosome 21 (iAMP21) identifies a high-risk subtype of acute lymphoblastic leukaemia (ALL), requiring intensive treatment to reduce their relapse risk. Improved understanding of the genomic landscape of iAMP21-ALL will ascertain whether these patients may benefit from targeted therapy. We performed whole-exome sequencing of eight iAMP21-ALL samples. The mutation rate was dramatically disparate between cases (average 24.9, range 5-51) and a large number of novel variants were identified, including frequent mutation of the RAS/MEK/ERK pathway. Targeted sequencing of a larger cohort revealed that 60% (25/42) of diagnostic iAMP21-ALL samples harboured 42 distinct RAS pathway mutations. High sequencing coverage demonstrated heterogeneity in the form of multiple RAS pathway mutations within the same sample and diverse variant allele frequencies (VAFs) (2-52%), similar to other subtypes of ALL. Constitutive RAS pathway activation was observed in iAMP21 samples that harboured mutations in the predominant clone (⩾35% VAF). Viable iAMP21 cells from primary xenografts showed reduced viability in response to the MEK1/2 inhibitor, selumetinib, in vitro. As clonal (⩾35% VAF) mutations were detected in 26% (11/42) of iAMP21-ALL, this evidence of response to RAS pathway inhibitors may offer the possibility to introduce targeted therapy to improve therapeutic efficacy in these high-risk patients.
PublisherNature Publishing Group
URLhttp://dx.doi.org/10.1038/leu.2016.80
DOI10.1038/leu.2016.80
PubMed id27168466
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