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BCL2L10 is a predictive factor for resistance to azacitidine in MDS and AML patients
Thomas Cluzeau1, Guillaume Robert, Nicolas Mounier
1INSERM U1065, Centre Mediterranéen de Médecine Moléculaire, Team Cell Death, Differentiation, Inflammation and Cancer, Nice, France.
Abstract:
Azacitidine is the leading compound to treat patients suffering myelodysplastic syndrome (MDS) or AML with less than 30% of blasts, but a majority of patients is primary refractory or rapidly relapses under treatment. These patients have a drastically reduced life expectancy as compared to sensitive patients. Therefore identifying predictive factors for AZA resistance is of great interest to propose alternative therapeutic strategies for non-responsive patients. We generated AZA-resistant myeloid cell line (SKM1-R) that exhibited increased expression of BCL2L10 an anti-apoptotic Bcl-2 member. Importantly, BCL2L10 knockdown sensitized SKM1-R cells to AZA effect suggesting that increased BCL2L10 expression is linked to AZA resistance in SKM1-R. We next established in 77 MDS patients that resistance to AZA is significantly correlated with the percentage of MDS or AML cells expressing BCL2L10. In addition, we showed that the proportion of BCL2L10 positive bone marrow cells can predict overall survival in MDS or AML patients. We propose a convenient assay in which the percentage of BCL2L10 expressing cells as assessed by flow cytometry is predictive of whether or not a patient will become resistant to AZA. Therefore, systematic determination of BCL2L10 expression could be of great interest in newly diagnosed and AZA-treated MDS patients.
Insights
Azacitidine resistance in myelodysplastic syndrome (MDS) and AML is linked to increased BCL2L10 expression. Measuring BCL2L10 levels can predict patient response and survival, guiding alternative therapies for non-responsive individuals.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Azacitidine is a key treatment for myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
- Many patients exhibit primary resistance or relapse, leading to poor prognoses.
- Identifying predictors of azacitidine resistance is crucial for developing alternative treatments.
Purpose of the Study:
- To identify predictive factors for azacitidine resistance in MDS and AML.
- To investigate the role of BCL2L10 in azacitidine resistance.
- To evaluate BCL2L10 expression as a prognostic marker in MDS and AML patients.
Main Methods:
- Generation of an azacitidine-resistant myeloid cell line (SKM1-R).
- Assessment of BCL2L10 expression in cell lines and patient samples via flow cytometry.
- Correlation analysis between BCL2L10 levels, azacitidine response, and patient survival in 77 MDS patients.
Main Results:
- Azacitidine-resistant SKM1-R cells showed increased BCL2L10 expression.
- BCL2L10 knockdown resensitized SKM1-R cells to azacitidine.
- Higher BCL2L10 expression in MDS/AML cells significantly correlated with azacitidine resistance.
- The proportion of BCL2L10-positive bone marrow cells predicted overall survival in MDS/AML patients.
Conclusions:
- Increased BCL2L10 expression is a key mechanism of azacitidine resistance.
- Flow cytometry assessment of BCL2L10 offers a predictive assay for azacitidine response.
- BCL2L10 determination is valuable for newly diagnosed and treated MDS patients.
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