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Blood, 11 June 2009, Vol. 113, No. 24, pp. 6182-6192.
Prepublished online as a Blood First Edition Paper on April 22, 2009; DOI 10.1182/blood-2008-12-194548.
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Submitted December 15, 2008
Accepted April 7, 2009
Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms
Francis H. Grand, Claire E. Hidalgo-Curtis, Thomas Ernst, Katerina Zoi, Christine Zoi, Carolann McGuire, Sebastian Kreil, Amy Jones, Joannah Score, Georgia Metzgeroth, David Oscier, Andrew Hall, Christian Brandts, Hubert Serve, Andreas Reiter, Andrew J. Chase, and Nicholas C.P. Cross*
Wessex Regional Genetics Laboratory, and Human Genetics Division, School of Medicine, University of Southampton, Salisbury, United Kingdom
Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece
Inflammation, Infection and Repair Division, School of Medicine, University of Southampton, Southampton, United Kingdom
III. Medizinische Universitatsklinik, Fakultat fur Klinische Medizin Mannheim der Universitat Heidelberg, Mannheim, Germany
Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom
Northern Institute for Cancer Research, Newcastle upon Tyne, United Kingdom
Department of Medicine, Hematology & Oncology, University of Frankfurt, Frankfurt, Germany
* Corresponding author; email: ncpc{at}soton.ac.uk.
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 (MPN), 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 polycythaemia vera (PV; n=10). Stretches of homozygous, copy neutral SNP calls >20Mb were seen in 10 (33%) aCML, 1 (6%) MF but absent in PV. In total seven different chromosomes were involved with 7q and 11q eah affected in 10% of aCML cases. CBL mutations were identified in all three 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 overexpressing FLT3. We conclude that acquired, transforming CBL mutations are a novel and widespread pathogenetic abnormality in morphologically-related, clinically aggressive MPNs.
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