title: Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.
abstract: Recent evidence has demonstrated that acquired uniparental disomy (aUPD) is a novel mechanism by which pathogenetic mutations in cancer may be reduced to homozygosity. To help identify novel mutations in myeloproliferative neoplasms (MPNs), we performed a genome-wide single nucleotide polymorphism (SNP) screen to identify aUPD in 58 patients with atypical chronic myeloid leukemia (aCML; n = 30), JAK2 mutation-negative myelofibrosis (MF; n = 18), or JAK2 mutation-negative polycythemia vera (PV; n = 10). Stretches of homozygous, copy neutral SNP calls greater than 20Mb were seen in 10 (33%) aCML and 1 (6%) MF, but were absent in PV. In total, 7 different chromosomes were involved with 7q and 11q each affected in 10% of aCML cases. CBL mutations were identified in all 3 cases with 11q aUPD and analysis of 574 additional MPNs revealed a total of 27 CBL variants in 26 patients with aCML, myelofibrosis or chronic myelomonocytic leukemia. Most variants were missense substitutions in the RING or linker domains that abrogated CBL ubiquitin ligase activity and conferred a proliferative advantage to 32D cells overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically related, clinically aggressive MPNs.
authors.affiliation: Wessex Regional Genetics Laboratory, Salisbury, United Kingdom.
authors.forename: Francis H
authors.initials: FH
authors.lastname: Grand
authors.forename: Claire E
authors.initials: CE
authors.lastname: Hidalgo-Curtis
authors.forename: Thomas
authors.initials: T
authors.lastname: Ernst
authors.forename: Katerina
authors.initials: K
authors.lastname: Zoi
authors.forename: Christine
authors.initials: C
authors.lastname: Zoi
authors.forename: Carolann
authors.initials: C
authors.lastname: McGuire
authors.forename: Sebastian
authors.initials: S
authors.lastname: Kreil
authors.forename: Amy
authors.initials: A
authors.lastname: Jones
authors.forename: Joannah
authors.initials: J
authors.lastname: Score
authors.forename: Georgia
authors.initials: G
authors.lastname: Metzgeroth
authors.forename: David
authors.initials: D
authors.lastname: Oscier
authors.forename: Andrew
authors.initials: A
authors.lastname: Hall
authors.forename: Christian
authors.initials: C
authors.lastname: Brandts
authors.forename: Hubert
authors.initials: H
authors.lastname: Serve
authors.forename: Andreas
authors.initials: A
authors.lastname: Reiter
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Chase
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D015894:Genome, Human; D055106:Genome-Wide Association Study; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology; D009196:Myeloproliferative Disorders / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D015996:Survival Rate; D024182:Uniparental Disomy / Q000235:genetics*; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D050721:Proto-Oncogene Proteins c-cbl; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2; C067419:CBL protein, human