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Gene expression-based prediction of myeloma cell sensitivity to histone deacetylase inhibitors
1CHU Montpellier, Institute of Research in Biotherapy, Montpellier, France.
Background:
Multiple myeloma (MM) is still a fatal plasma cell cancer. Novel compounds are currently clinically tested as a single agent in relapsing patients, but in best cases with partial response of a fraction of patients, emphasising the need to design tools predicting drug efficacy. Histone deacetylase inhibitors (HDACi) are anticancer agents targeting epigenetic regulation of gene expression and are in clinical development in MM.
Methods:
To create a score predicting HDACi efficacy, five MM cell lines were treated with trichostatin A (TSA) and gene expression profiles were determined.
Results:
The expression of 95 genes was found to be upregulated by TSA, using paired supervised analysis with Significance Analysis of Microarrays software. Thirty-seven of these 95 genes had prognostic value for overall survival in a cohort of 206 newly diagnosed MM patients and their prognostic information was summed up in a histone acetylation score (HA Score); patients with the highest HA Score had the shorter overall survival. It is worth noting that MM cell lines or patients' primary MM cells with a high HA Score had a significant higher sensitivity to TSA, valproic acid, panobinostat or vorinostat.
Conclusion:
In conclusion, the HA Score allows identification of MM patients with poor survival, who could benefit from HDACi treatment.
Insights
A new histone acetylation score (HA Score) predicts which multiple myeloma patients may benefit from histone deacetylase inhibitors (HDACi). High HA Score indicates poor survival but increased sensitivity to HDACi drugs.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- Multiple myeloma (MM) is a fatal plasma cell cancer with limited treatment options for relapsing patients.
- Novel therapeutic strategies, including histone deacetylase inhibitors (HDACi), are under investigation for MM.
- Predictive tools are needed to identify patients likely to respond to specific treatments.
Purpose of the Study:
- To develop a predictive score for histone deacetylase inhibitor (HDACi) efficacy in multiple myeloma (MM).
- To identify a gene expression signature associated with HDACi response and patient survival.
Main Methods:
- Gene expression profiling of five MM cell lines treated with trichostatin A (TSA).
- Supervised analysis using Significance Analysis of Microarrays (SAM) to identify upregulated genes.
- Development of a histone acetylation score (HA Score) based on prognostic gene expression.
Main Results:
- TSA upregulated 95 genes in MM cell lines.
- Thirty-seven genes with prognostic value for overall survival were identified.
- A high HA Score correlated with shorter overall survival but increased sensitivity to HDACi (TSA, valproic acid, panobinostat, vorinostat).
Conclusions:
- The HA Score can identify multiple myeloma patients with poor prognosis.
- Patients with a high HA Score may benefit from histone deacetylase inhibitor (HDACi) therapy.
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