title: Mutation of genes affecting the RAS pathway is common in childhood acute lymphoblastic leukemia.
abstract: Deregulation of the RAS-RAF-mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK signaling cascade is often caused by somatic mutations in genes encoding proteins which influence the activity of this pathway and include NRAS, KRAS2, FLT3, PTPN11, and BRAF. We report the first comprehensive mutational screen of key exons of these genes in a large cohort of unselected acute lymphoblastic leukemia (ALL) cases at diagnosis (n = 86) and in a more selected cohort at disease recurrence (n = 47) using the sensitive method of denaturing high-performance liquid chromatography. We show that somatic mutations that deregulate the pathway constitute one of the most common genetic aberrations in childhood ALL (cALL), being found in 35% of diagnostic and 25% of relapse samples. In matched presentation/relapse pairs, mutations predominating at relapse could be shown to be present at very low levels at diagnosis using allele-specific PCR, thus implicating the mutated clone in disease progression. Importantly, in primary samples, we show that mutations are associated with activated ERK and differential cytotoxicity to MEK-ERK inhibitors was shown for some patients. Inhibitors of the pathway, which are currently undergoing clinical trial, may be a novel therapeutic option for cALL, particularly at relapse.
authors.affiliation: Northern Institute for Cancer Research, Newcastle upon Tyne, Tyne and Wear, United Kingdom.
authors.forename: Marian
authors.initials: M
authors.lastname: Case
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matheson
authors.forename: Lynne
authors.initials: L
authors.lastname: Minto
authors.forename: Rosline
authors.initials: R
authors.lastname: Hassan
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Harrison
authors.forename: Nick
authors.initials: N
authors.lastname: Bown
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: Josef
authors.initials: J
authors.lastname: Vormoor
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Hall
authors.forename: Julie A E
authors.initials: JA
authors.lastname: Irving
mesh_terms: D000293:Adolescent; D015153:Blotting, Western; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005091:Exons / Q000235:genetics; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D011905:Genes, ras / Q000502:physiology*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000473:pathology; D010446:Peptide Fragments; D011003:Ploidies; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000473:pathology; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012074:Remission Induction; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics; D018631:ras Proteins / Q000235:genetics*
chemical_list: D004791:Enzyme Inhibitors; C117307:KRAS protein, human; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins