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

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.

Role of non-coding RNA networks in leukemia progression, metastasis and drug resistance

“…Numerous lncRNAs are deregulated in different sorts of malignant growths, including head and neck cancer [92]. Unmistakable expression profiles of lncRNA have been distinguished in leukemia [9,33,35,45,[47][48][49][93][94][95][96][97][98][99]. Some of these have been demonstrated to have wellunderstood jobs in the development and progression of leukemia, suggesting the vital use of lncRNAs as novel biomarkers and potential targets for the treatment of leukemia.…”

Non-Coding RNAs as Cancer Hallmarks in Chronic Lymphocytic Leukemia

“…Another lncRNA, treRNA, is highly expressed in patients with aggressive CLL, bearing poor prognostic indicators such as unmutated IGHV and high ZAP70 protein expression. In this set of patients, treRNA expression is associated with shorter PFS and OS, and a low expression of treRNA has been proven to be an independent prognostic factor for improved PFS in patients receiving fludarabine plus cyclophosphamide [53] BGL3 (beta globin locus transcript 3) is a 3.6-kb lncRNA derived from chromosome 11p15.4. BGL3 expression in leukemic cells is negatively regulated by Bcr-Abl through c-Myc-mediated DNA methylation [54].…”

Long Non-Coding RNAs Guide the Fine-Tuning of Gene Regulation in B-Cell Development and Malignancy

“…A microarray study identified eight lncRNAs differentially expressed in CLL patients compared to controls. One of these, translation regulatory long non-coding RNA1 (treRNA1) was significantly higher expressed in unmutated IGHV samples [ 95 ], and served as an independent prognostic marker for shorter PFS in patients receiving fludarabine and cyclophosphamide. Overexpression of treRNA1 in a CLL cell line led to reduced cell death, suggesting that treRNA1 decreases DNA damage and sensitivity to chemotherapy, thereby explaining the shorter PFS.…”