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The role of the RAS pathway in iAMP21-ALL

Lookup NU author(s): Dr Sarra Ryan, Elizabeth Matheson, Dr Paul Sinclair, Dr Matthew Bashton, Claire Schwab, Dr Matthew Partington, Alannah Elliott, Lynne Minto, Stacey Richardson, Dr Thahira Rahman, Professor Bernard Keavney, Professor Roderick Skinner, Dr Nicholas Bown, Dr Mauro Santibanez Koref, Professor Anthony Moorman, Professor Julie Irving, Professor Christine Harrison

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

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.


Publication metadata

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

Publication status: Published

Journal: Leukemia

Year: 2016

Volume: 30

Pages: 1824-1831

Online publication date: 22/04/2016

Acceptance date: 22/03/2016

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/leu.2016.80

DOI: 10.1038/leu.2016.80

PubMed id: 27168466


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