Identification of a novel tRNA-derived RNA fragment exhibiting high prognostic potential in chronic lymphocytic leukemia

Paraskevi Karousi, Katerina Katsaraki, Sotirios G Papageorgiou, Vasiliki Pappa, Andreas Scorilas, Christos K Kontos
Hematological Oncology 2019 April 4
tRNA-derived fragments (tRFs) are 16-28 nucleotide fragments, which occur by specific cleavage of tRNA molecules. i-tRF-GlyGCC is an internal tRF, originating from the tRNAs bearing the Glycine anticodon "GCC". Other tRFs generated from tRNAGlyGCC have proved to be associated with various cancer types. Chronic lymphocytic leukemia (CLL) is a type of leukemia during which CD5+ B lymphocytes accumulate in marrow and lymphoid tissues and is characterized by differential clinical features among patients. In this original study, we verified the existence of this tRF experimentally, and examined, for the first time, the putative utility of this molecule as a prognostic biomarker in CLL, by developing an innovative tRF quantification method, based on the SYBR chemistry. Total RNA was extracted from peripheral blood mononuclear cells (PBMCs) collected from 91 CLL patients and 43 non-leukemic blood donors. In vitro polyadenylation and reverse transcription using an oligo-dT-adapter were carried out and quantitative expression analysis of i-tRF-GlyGCC was performed by an in-house-developed real-time quantitative PCR assay. Advanced biostatistical analysis followed, to assess our results. As revealed by Kaplan-Meier survival analysis, elevated levels of i-tRF-GlyGCC were associated with poor overall survival of CLL patients (p<0.001). Univariate bootstrap Cox regression analysis confirmed these results, by demonstrating a higher hazard ratio (HR) of 3.40 (95% CI=1.6-7.18, p=0.001) for patients overexpressing for i-tRF-GlyGCC, compared to patients with lower expression levels. Multivariate bootstrap Cox regression analysis revealed that the prognostic value of this tRF is independent of clinical stage, IGHV mutational status and CD38 expression (Binet or Rai stage: p<0.001. risk group, p=0.001; bootstrapping p=0.003 and p=0.004 respectively). Our findings demonstrate that the expression status of i-tRF-GlyGCC could serve as potential indicator of unfavorable prognosis in this hematological malignancy, as its prognostic significance is independent of other established prognostic factors in CLL.

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