De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with myeloid differentiation pathways
Files
Date
2019
Authors
Magistroni, V.
Mauri, M.
D'Aliberti, D.
Mezzatesta, C.
Crespiatico, I.
Nava, M.
Fontana, D.
Sharma, N.
Parker, W.
Schreiber, A.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
Haematologica, 2019; 104(9):1789-1797
Statement of Responsibility
Conference Name
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 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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
Copyright 2019 Fondazione Ferrata Storti. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode,sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. (https://creativecommons.org/licenses/by-nc/4.0/legalcode)