Oncotarget

Research Papers:

The long noncoding RNA, treRNA, decreases DNA damage and is associated with poor response to chemotherapy in chronic lymphocytic leukemia

Cecelia R. Miller, Amy S. Ruppert, Sydney Fobare, Timothy L. Chen, Chaomei Liu, Amy Lehman, James S. Blachly, Xiaoli Zhang, David M. Lucas, Michael R. Grever, Martin S. Tallman, Ian W. Flinn, Laura Z. Rassenti, Thomas J. Kipps, Deepa Sampath, Kevin R. Coombes and Erin K. Hertlein _

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Oncotarget. 2017; 8:25942-25954. https://doi.org/10.18632/oncotarget.15401

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Abstract

Cecelia R. Miller1, Amy S. Ruppert1, Sydney Fobare1,2, Timothy L. Chen1, Chaomei Liu3, Amy Lehman4, James S. Blachly1, Xiaoli Zhang4, David M. Lucas1, Michael R. Grever1, Martin S. Tallman5, Ian W. Flinn6, Laura Z. Rassenti7,9, Thomas J. Kipps7,9, Deepa Sampath1, Kevin R. Coombes8,* and Erin K. Hertlein1,*

1 Department of Internal Medicine, Division of Hematology, Comprehensive Cancer Center at The Ohio State University, Columbus, OH, USA

2 Hendrix College, Conway, AR, USA

3 Department of Experimental Therapeutics, MD Anderson Cancer Center at University of Texas, Houston, TX, USA

4 Center for Biostatistics, The Ohio State University, Columbus, OH, USA

5 Memorial Sloan Kettering Cancer Center, New York, NY, USA

6 Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA

7 Department of Medicine, Moores Cancer Center at University of California at San Diego, La Jolla CA, USA

8 Department of Biomedical Informatics, The Ohio State University, Columbus, OH, USA

9 The Chronic Lymphocytic Leukemia (CLL) Research Consortium, La Jolla, CA, USA

* These authors have contributed equally to this work

Correspondence to:

Erin Hertlein, email:

Keywords: lncRNA, treRNA, chronic lymphocytic leukemia, DNA damage, prognostic factor

Received: January 26, 2017 Accepted: January 30, 2017 Published: February 16, 2017

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.


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