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The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic
Cecelia R Miller1, Amy S Ruppert1, Sydney Fobare1,2
1Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA.
Abstract:
The study of long noncoding RNAs (lncRNAs) is an emerging area of cancer research, in part due to their ability to serve as disease biomarkers. However, few studies have investigated lncRNAs in chronic lymphocytic leukemia (CLL). We have identified one particular lncRNA, treRNA, which is overexpressed in CLL B-cells. We measured transcript expression in 144 CLL patient samples and separated samples into high or low expression of treRNA relative to the overall median. We found that high expression of treRNA is significantly associated with shorter time to treatment. High treRNA also correlates with poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. We validated these initial findings in samples collected in a clinical trial comparing the nucleoside analog fludarabine alone or in combination with the alkylating agent cyclophosphamide in untreated CLL samples collected prior to starting therapy (E2997). High expression of treRNA was independently prognostic for shorter progression free survival in patients receiving fludarabine plus cyclophosphamide. Given these results, in order to study the role of treRNA in DNA damage response we generated a model cell line system where treRNA was over-expressed in the human B-CLL cell line OSU-CLL. Relative to the vector control line, there was less cell death in OSU-CLL over-expressing treRNA after exposure to fludarabine and mafosfamide, due in part to a reduction in DNA damage. Therefore, we suggest that treRNA is a novel biomarker in CLL associated with aggressive disease and poor response to chemotherapy through enhanced protection against cytotoxic mediated DNA damage.
Insights
A novel long noncoding RNA, treRNA, is overexpressed in chronic lymphocytic leukemia (CLL) and linked to aggressive disease. High treRNA expression predicts poor treatment response by protecting cancer cells from chemotherapy-induced DNA damage.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Long noncoding RNAs (lncRNAs) are increasingly recognized as potential cancer biomarkers.
- Research into lncRNAs in chronic lymphocytic leukemia (CLL) remains limited.
- This study focuses on the role of a specific lncRNA, treRNA, in CLL.
Purpose of the Study:
- To investigate the role of treRNA as a biomarker in chronic lymphocytic leukemia (CLL).
- To determine the association between treRNA expression levels and disease progression and treatment response in CLL patients.
- To explore the functional impact of treRNA on cellular response to DNA damage and chemotherapy.
Main Methods:
- Quantitative measurement of treRNA transcript expression in 144 CLL patient samples.
- Correlation analysis of treRNA expression with clinical parameters like time to treatment, IGHV mutation status, and ZAP70 expression.
- Validation of treRNA's prognostic value in a clinical trial cohort (E2997) treated with fludarabine and cyclophosphamide.
- Generation of a CLL cell line model overexpressing treRNA to study its effect on DNA damage response and cell viability after cytotoxic drug exposure.
Main Results:
- TreRNA was found to be overexpressed in CLL B-cells.
- High treRNA expression significantly correlated with shorter time to treatment and poor prognostic indicators (unmutated IGHV, high ZAP70).
- In a clinical trial, high treRNA independently predicted shorter progression-free survival in patients receiving fludarabine plus cyclophosphamide.
- Overexpression of treRNA in a CLL cell line reduced cell death and DNA damage following exposure to fludarabine and mafosfamide.
Conclusions:
- TreRNA is a novel, overexpressed lncRNA biomarker in CLL associated with aggressive disease.
- High treRNA expression is linked to poor prognosis and reduced response to chemotherapy.
- TreRNA may confer chemoresistance by enhancing protection against cytotoxic-mediated DNA damage in CLL cells.
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