Dysregulation of different classes of tRNA fragments in chronic lymphocytic leukemia

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作   者：

Veneziano, Dario;  Tomasello, Luisa;  Balatti, Veronica;  Palamarchuk, Alexey;  Rassenti, Laura Z.;  Kipps, Thomas J.;  Pekarsky, Yuri;  Croce, Carlo M.; 

作者机构：

CA 92093 USA;  Dept Med;  Columbus;  Univ Calif San Diego;  OH 43210 USA;  Ohio State Univ;  La Jolla;  Dept Canc Biol & Genet; 

关键词：

tsRNAs;  NONCODING RNA;  tRNA fragments;  tRFs;  PROGRESSION;  MICRORNA; 

期刊名称：

Proceedings of the National Academy of Sciences of the United States of America.

i s s n：

0027-8424

年卷期：

2019 年 116 卷 48 期

页   码：

24252-24258

页   码：

摘   要：

Chronic lymphocytic leukemia (CLL) is the most common human leukemia, and dysregulation of tRNA-derived short noncoding RNA (t5RNA) (tRF-1) expression is an accompanying event in the development of this disease. tsRNAs are fragments originating from the 3' end of tRNA precursors and do not contain mature tRNA sequences. In contrast to tsRNAs, mature tRFs (tRF-3s, tRF5s, and internal tRFs) are produced from mature tRNA sequences and are redundant fragments. We investigated t5RNA expression in CLL and determined t5RNA signatures in indolent CLL and aggressive CLL vs. normal B cells. We noticed that both is-43 and is-44 are derived from distinct genes of pre-tRNA(His), and are downregulated in CLL 3- to 5-fold vs. normal B cells. Thus, we investigated expression levels of tRF-5 fragments from tRNA(His) in CLL samples and healthy controls, and determined that such fragments are down-regulated by 5-fold in CLL5 vs. normal controls. Given these results, we investigated the expression of all mature tRFs in CLL5 vs. normal controls. We found a drastic dysregulation of the expression of mature tRFs in CLL. In aggressive CLL, for the top 15 up-regulated fragments, linear fold change varied from 2,053- to 622-fold. For the top 15 down-regulated fragments in CLL, linear fold change varied from 314- to 52-fold. In addition, 964 mature tRFs were up-regulated at least 2-fold in CLL, while 701 fragments were down-regulated at least 2-fold. Similar results were obtained for indolent CLL. Our results suggest that mature tRFs may have oncogenic and/or tumor suppressor function in CLL.