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Haematologica. 2019 Sep;104(9):1789-1797. doi: 10.3324/haematol.2017.179937. Epub 2019 Feb 28.

De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways.

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Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy
Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy.
Center for Cancer Biology, SA Pathology, Adelaide, Australia.
University of Adelaide, South Australia, Australia.
GalSeq s.r.l., Monza, Italy.
Department of Bioscience and Biotechnology, University of Milano Bicocca, Milano, Italy.
Bloodwise Molecular Haematology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK.
NIHR Biomedical Research Centre, Oxford, UK.
Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy.
Department of Hematology, Catholic University, Seoul, South Korea.
University of South Australia, Adelaide, South Australia, Australia.
Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy.
Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy


Despite the advent of tyrosine kinase inhibitors, a proportion of chronic myeloid leukemia patients in chronic phase fail to respond to imatinib or to second-generation inhibitors and progress to blast crisis. Until now, improvements in the understanding of the molecular mechanisms responsible for chronic myeloid leukemia transformation from chronic phase to the aggressive blast crisis remain limited. Here we present a large parallel sequencing analysis of 10 blast crisis samples and of the corresponding autologous chronic phase controls that reveals, for the first time, recurrent mutations affecting the ubiquitin-conjugating enzyme E2A gene (UBE2A, formerly RAD6A). Additional analyses on a cohort of 24 blast crisis, 41 chronic phase as well as 40 acute myeloid leukemia and 38 atypical chronic myeloid leukemia patients at onset confirmed that UBE2A mutations are specifically acquired during chronic myeloid leukemia progression, with a frequency of 16.7% in advanced phases. In vitro studies show that the mutations here described cause a decrease in UBE2A activity, leading to an impairment of myeloid differentiation in chronic myeloid leukemia cells.

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