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

作者：Francis Grand, Claire Hidalgo-Curtis, Thomas Ernst, Katerina Zoi, Christine Zoi, Carolann McGuire, Sebastian Kreil, Amy V. Jones, J Score, Georgia Metzgeroth, David Graham Oscier, Andrew G. Hall, Christian Brandts, Hubert L. Serve, Andreas Reiter, Andrew Chase, Nicholas C.P. Cross · 发表于：Blood · 年份：2009 · DOI：10.1182/blood-2008-12-194548 · 被引用次数：378 · 研究领域：Myeloproliferative Neoplasms: Diagnosis and Treatment、Chronic Myeloid Leukemia Treatments、Acute Myeloid Leukemia Research

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.