title: The role of the RAS pathway in iAMP21-ALL.
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.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: S L
authors.initials: SL
authors.lastname: Ryan
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: E
authors.initials: E
authors.lastname: Matheson
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: V
authors.initials: V
authors.lastname: Grossmann
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: P
authors.initials: P
authors.lastname: Sinclair
authors.affiliation: Bioinformatics Support Unit, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Bashton
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: C
authors.initials: C
authors.lastname: Schwab
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: W
authors.initials: W
authors.lastname: Towers
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Partington
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: A
authors.initials: A
authors.lastname: Elliott
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: L
authors.initials: L
authors.lastname: Minto
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: S
authors.initials: S
authors.lastname: Richardson
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: T
authors.initials: T
authors.lastname: Rahman
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle Upon Tyne, UK.|Institute of Cardiovascular Sciences, The University of Manchester, Manchester, UK.
authors.forename: B
authors.initials: B
authors.lastname: Keavney
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: R
authors.initials: R
authors.lastname: Skinner
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: N
authors.initials: N
authors.lastname: Bown
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Haferlach
authors.affiliation: Center for Human Genetics, University Hospital Leuven and KU Leuven, Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Vandenberghe
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Haferlach
authors.affiliation: Institute of Human Genetics, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Santibanez-Koref
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: A V
authors.initials: AV
authors.lastname: Moorman
authors.affiliation: MLL Munich Leukemia Laboratory, Munich, Germany.|AstraZeneca, Personalized Healthcare and Biomarkers, Innovative Medicines, Macclesfield, UK.
authors.forename: A
authors.initials: A
authors.lastname: Kohlmann
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: J A E
authors.initials: JA
authors.lastname: Irving
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Newcastle Upon Tyne, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Harrison
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology; D002470:Cell Survival; D002869:Chromosome Aberrations; D002891:Chromosomes, Human, Pair 21; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics*; D051379:Mice; D059645:Mutation Rate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; D018631:ras Proteins