title: Casitas B lymphoma mutations in childhood acute lymphoblastic leukemia.
abstract: Casitas B-lineage lymphoma (CBL) proteins are RING finger ubiquitin E3 ligases that attenuate the signaling of receptor tyrosine kinases and are mutated in a number of myeloid disorders. In this study, mutational screening of the linker-RING domains of CBL and CBLB was performed by denaturing high performance liquid chromatography in a cohort of diagnostic (n = 180) or relapse (n = 46) samples from children with acute lymphoblastic leukemia. Somatic mutations were identified in three children, giving an overall incidence of 1.7% and involved small deletions affecting the intron/exon boundaries of exon 8, leading to skipping of exon 8 and abolishing E3 ligase function. Mutated primary samples were associated with constitutive activation of the RAS pathway and sensitivity to MEK inhibitors was shown. Thus, mutation of CBL is an alternative route to activate the RAS pathway and may identify children who are candidates for MEK inhibitor clinical trials.
authors.affiliation: Paediatric Oncology and Haematology Group, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: Lindsay
authors.initials: L
authors.lastname: Nicholson
authors.forename: Thomas
authors.initials: T
authors.lastname: Knight
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Matheson
authors.forename: Lynne
authors.initials: L
authors.lastname: Minto
authors.forename: Marian
authors.initials: M
authors.lastname: Case
authors.forename: Maryna
authors.initials: M
authors.lastname: Sanichar
authors.forename: Simon
authors.initials: S
authors.lastname: Bomken
authors.forename: Josef
authors.initials: J
authors.lastname: Vormoor
authors.forename: Andy
authors.initials: A
authors.lastname: Hall
authors.forename: Julie
authors.initials: J
authors.lastname: Irving
mesh_terms: D000293:Adolescent; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002853:Chromatography, Liquid; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D006801:Humans; D007438:Introns; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D050722:Oncogene Protein v-cbl / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D054829:RING Finger Domains; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D012008:Recurrence; D015398:Signal Transduction / Q000235:genetics*; D006113:United Kingdom
chemical_list: D050722:Oncogene Protein v-cbl; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases; D020930:MAP Kinase Kinase Kinases