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Chronic Myeloid Leukemia
De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways
Ferrata Storti Foundation
Haematologica 2019 Volume 104(9):1789-1797
Vera Magistroni,1* Mario Mauri,1* Deborah D’Aliberti,1 Caterina Mezzatesta,1 Ilaria Crespiatico,1 Miriam Nava,1 Diletta Fontana,1 Nitesh Sharma,1
Wendy Parker,2 Andreas Schreiber,2 David Yeung,2,3 Alessandra Pirola,4 Sara Readelli,1 Luca Massimino,1 Paul Wang,2 Praveen Khandelwal,1 Stefania Citterio,5 Michela Viltadi,1 Silvia Bombelli,1 Roberta Rigolio,1 Roberto Perego,1 Jacqueline Boultwood,6,7 Alessandro Morotti,8
Giuseppe Saglio,8 Dong-Wook Kim,9 Susan Branford,2,3,10 Carlo Gambacorti-Passerini1,11** and Rocco Piazza1**
1Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy; 2Center for Cancer Biology, SA Pathology, Adelaide, Australia; 3University of Adelaide, South Australia, Australia; 4GalSeq s.r.l., Monza, Italy; 5Department of Bioscience and Biotechnology, University of Milano Bicocca, Milano, Italy; 6Bloodwise Molecular Haematology Unit, John Radcliffe Hospital, University of Oxford, Oxford, UK; 7NIHR Biomedical Research Centre, Oxford, UK; 8Department of Clinical and Biological Sciences, San Luigi Hospital, University of Turin, Turin, Italy; 9Department of Hematology, Catholic University, Seoul, South Korea; 10University of South Australia, Adelaide, South Australia, Australia and 11Hematology and Clinical Research Unit, San Gerardo Hospital, Monza, Italy
*VM and MM contributed equally to this work. **RP and CGP contributed equally to this work
ABSTRACT
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 muta- tions 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.
Introduction
Chronic myeloid leukemia (CML) is a myeloproliferative disorder with an inci- dence of 1-2 cases per 100,000/year. It is characterized by the presence of the BCR-ABL1 fusion gene, the product of the reciprocal translocation between chro- mosomes 9 and 22.1 After the translocation, the coding regions of BCR and ABL1 genes are juxtaposed, leading to an enhanced ABL1 tyrosine kinase activity.2 CML is a multi-step disease, evolving from a mild form that is easy to control, called chronic phase (CP), to a very aggressive and incurable acute phase called blast cri- sis (BC). The majority of CML-CP patients are successfully treated with drugs able to impair BCR-ABL1 kinase activity (tyrosine kinase inhibitors, TKI), thus confirming the central role of the oncogenic fusion protein in CML pathogene-
Correspondence:
VERA MAGISTRONI
vera.magistroni@unimib.it
ROCCO PIAZZA
rocco.piazza@unimib.it
Received: January 19, 2018. Accepted: February 26, 2019. Pre-published: February 28, 2019.
doi:10.3324/haematol.2017.179937
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1789
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