Comprehensive miRNA expression profiling in human T-cell acute lymphoblastic leukemia by small RNA-sequencing

Annelynn Wallaert,Frank Speleman,Lucie Hernandez,Wouter Van Loocke,Pieter Van Vlierberghe,Tom Taghon

doi:10.1038/s41598-017-08148-x

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a genetically heterogeneous disease that can be classified into different molecular genetic subtypes according to their mRNA gene expression profile. In this study, we applied RNA sequencing to investigate the full spectrum of miRNA expression in primary T-ALL patient samples, T-ALL leukemia cell lines and healthy donor thymocytes. Notably, this analysis revealed that genetic subtypes of human T-ALL also display unique miRNA expression signatures, which are largely conserved in human T-ALL cell lines with corresponding genetic background. Furthermore, small RNA-sequencing also unraveled the variety of isoforms that are expressed for each miRNA in T-ALL and showed that a significant number of miRNAs are actually represented by an alternative isomiR. Finally, comparison of CD34+ and CD4+CD8+ healthy donor thymocytes and T-ALL miRNA profiles allowed identifying several novel miRNAs with putative oncogenic or tumor suppressor functions in T-ALL. Altogether, this study provides a comprehensive overview of miRNA expression in normal and malignant T-cells and sets the stage for functional evaluation of novel miRNAs in T-ALL disease biology.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is classified into different genetic subtypes based upon the aberrant expression of specific transcription factor oncogenes (TAL, TLX1, TLX3 or HOXA) or the arrest at a specific stage of T-cell differentiation[1,2,3,4]
To study the full spectrum of miRNAs involved in normal and malignant T-cell development, we performed small RNA-sequencing on 48 primary T-ALL patient samples of different T-ALL subgroups (13 immature, TLX1+ or TLX3+, TAL-rearranged and 6 HOXA-overexpressing T-ALL samples), CD34+ and CD4+CD8+ normal thymocyte subsets from healthy donors and a panel of 7 T-ALL cell lines (Fig. 1a)
We were able to show that these molecular genetic subtypes of human T-ALL display unique long non-coding RNA expression signatures[5]

Summary

Introduction

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that is classified into different genetic subtypes based upon the aberrant expression of specific transcription factor oncogenes (TAL, TLX1, TLX3 or HOXA) or the arrest at a specific stage of T-cell differentiation (immature T-ALL)[1,2,3,4] These molecular subgroups are characterized by unique mRNA and long non-coding RNA expression signatures, which partially reflect their putative cell of origin[1, 2, 5]. Small RNA-sequencing emerged as a more comprehensive technology that enables unbiased detection of the full spectrum of small RNA molecules It provides information on specific isoforms that differ from canonical miRNAs by the addition or deletion of one or more nucleotides at the 5′ or 3′ end of the miRNA11, 12. In malignant T-cells and use small RNA sequencing profiles of normal T-cell subsets to identify novel putative oncogenic or tumor suppressive miRNAs in the context of human T-ALL

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