Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms.
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.
Grand
Francis H
FH
Wessex Regional Genetics Laboratory, Salisbury, United Kingdom.
Hidalgo-Curtis
Claire E
CE
Ernst
Thomas
T
Zoi
Katerina
K
Zoi
Christine
C
McGuire
Carolann
C
Kreil
Sebastian
S
Jones
Amy
A
Score
Joannah
J
Metzgeroth
Georgia
G
Oscier
David
D
Hall
Andrew
A
Brandts
Christian
C
Serve
Hubert
H
Reiter
Andreas
A
Chase
Andrew J
AJ
Cross
Nicholas C P
NC
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
D050721:Proto-Oncogene Proteins c-cbl; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D053614:Janus Kinase 2; C067419:CBL protein, human