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Updated: Jan 28, 2026
Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up
Published on: March 26, 2018
De novo UBE2A mutations are recurrently acquired during chronic myeloid leukemia progression and interfere with
Vera Magistroni1, Mario Mauri2, Deborah D'Aliberti2
1Department of Medicine and Surgery, University of Milano Bicocca, Monza, Italy vera.magistroni@unimib.it.
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.
Insights
New research identifies specific mutations in the ubiquitin-conjugating enzyme E2A gene (UBE2A) as a key factor in chronic myeloid leukemia (CML) progression to blast crisis. These UBE2A mutations impair myeloid differentiation, offering potential new therapeutic targets for advanced CML.
Area of Science:
- Hematology
- Molecular Biology
- Oncology
Background:
- Chronic myeloid leukemia (CML) treatment faces challenges with imatinib resistance and progression to blast crisis.
- Molecular mechanisms underlying CML transformation from chronic phase to blast crisis are not fully understood.
Purpose of the Study:
- To investigate the molecular basis of CML progression to blast crisis.
- To identify genetic alterations associated with CML transformation.
Main Methods:
- Large-scale parallel sequencing of CML blast crisis and chronic phase samples.
- Analysis of UBE2A gene mutations in patient cohorts.
- In vitro functional studies of UBE2A mutations.
Main Results:
- Recurrent mutations in the ubiquitin-conjugating enzyme E2A gene (UBE2A) were identified in CML blast crisis samples.
- UBE2A mutations were specifically acquired during CML progression, found in 16.7% of advanced phase patients.
- These mutations decrease UBE2A activity, impairing myeloid differentiation in CML cells.
Conclusions:
- UBE2A mutations are a significant molecular event in CML progression to blast crisis.
- Impaired myeloid differentiation due to UBE2A dysfunction contributes to disease advancement.
- Targeting UBE2A may offer novel therapeutic strategies for advanced CML.
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