A novel, mitochondrial, internal tRNA-derived RNA fragment possesses clinical utility as a molecular prognostic biomarker in chronic lymphocytic leukemia
Authors: Sotirios G Papageorgiou
Andreas Scorilas
Panagiotis G Adamopoulos
Christos K Kontos
Paraskevi Karousi
Vasiliki Pappa
Journal: Clinical biochemistry (2020)
Discipline: CLINICAL MEDICINE
Keywords: B-cell lymphoid malignancies; CLL; Prognosticator; Real-time qPCR; Unfavorable prognosis
Affiliations: Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens GR-15701, Greece., Second Department of Internal Medicine and Research Unit, University General Hospital "Attikon", 1 Rimini St., Haidari, GR 12462 Athens, Greece., Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian University of Athens, Athens GR-15701, Greece. Electronic address: .

Abstract:  Objectives: Chronic lymphocytic leukemia (CLL) is the most common leukemia among adults. The prognosis of CLL patients varies considerably. Transfer RNA-derived RNA fragments (tRFs) constitute a class of small non-coding RNA fragments excised from mature tRNAs and pre-tRNAs located in nuclei as well as in mitochondria. In this study, the clinical utility of i-tRF-PheGAA, a novel mitochondrial tRF, was investigated in CLL. Design and methods: Peripheral blood mononuclear cells (PBMCs) were isolated from 91 CLL patients and 43 non-leukemic controls. Total RNA was isolated from each sample, polyadenylated at the 3' end and reversely transcribed. An in-house developed real-time quantitative PCR assay was developed and applied, and the results were biostatistically analyzed. For the normalization of the i-tRF-PheGAA expression levels, the expression of a small nucleolar RNA (RNU48) was used as reference. Results: Mann-Whitney U test showed that i-tRF-PheGAA can distinguish between CLL samples and normal controls (p &lt; 0.001). As determined by Kaplan-Meier survival analysis, overexpression of i-tRF-PheGAA was related to poor overall survival of the CLL patients (p &lt; 0.001). Univariate bootstrap Cox regression analysis exhibited a higher hazard ratio of 7.95 (95% CI = 2.37-26.72, p &lt; 0.001) for patients with positive i-tRF-PheGAA expression status. Multivariate bootstrap Cox regression analysis showed that the prognostic value of this tRF is independent of clinical stage, mutational status of the immunoglobulin heavy chain variable (IGHV) genetic locus, and CD38 expression status (p = 0.010). Conclusions: Our results show that i-tRF-PheGAA can serve as a molecular biomarker of poor prognosis in CLL, alongside with the existing factors for CLL prognosis. 

Retracted: No

PubPeer comments:
 Authors are showing reduced expression of a certain i-tRF in CLL PBMCs vs. healthy PBMCs.  Authors are not discussing possible specific explanations for the comparatively decreased expression of this tRF in their CCL PBMCs vs. Healthy PBMCs.  However, an earlier study Blood . 2019 Jul 4;134(1):44-58. , in Fig.5C. has shown that CLL PBMCs contain less mitochondrial mass, as examined with mito-tracker.  Hence, question arises if the lesser expression can be explained with less mitochondrial mass in CLL PBMCs compared to Healthy PBMC donors. Could the authors indicate if they checked for this? ,