Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms

Author:

Grand Francis H.1,Hidalgo-Curtis Claire E.1,Ernst Thomas1,Zoi Katerina2,Zoi Christine2,McGuire Carolann3,Kreil Sebastian1,Jones Amy1,Score Joannah1,Metzgeroth Georgia4,Oscier David5,Hall Andrew6,Brandts Christian7,Serve Hubert7,Reiter Andreas4,Chase Andrew J.1,Cross Nicholas C. P.1

Affiliation:

1. Wessex Regional Genetics Laboratory, Salisbury, and Human Genetics Division, School of Medicine, University of Southampton, Southampton, United Kingdom;

2. Haematology Research Laboratory, Biomedical Research Foundation, Academy of Athens, Athens, Greece;

3. Inflammation, Infection and Repair Division, School of Medicine, University of Southampton, Southampton, United Kingdom;

4. III Medizinische Universitätsklinik, Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim, Germany;

5. Department of Haematology, Royal Bournemouth Hospital, Bournemouth, United Kingdom;

6. Northern Institute for Cancer Research, Newcastle upon Tyne, United Kingdom; and

7. Department of Medicine, Hematology & Oncology, University of Frankfurt, Frankfurt, Germany

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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