Long Noncoding RNAs in Acute Myeloid Leukemia: Functional Characterization and Clinical Relevance

Abstract

Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults with an incidence of 4.3 per 100,000 cases per year. Historically, the identification of genetic alterations in AML focused on protein-coding genes to provide biomarkers and to understand the molecular complexity of AML. Despite these findings and because of the heterogeneity of this disease, questions as to the molecular mechanisms underlying AML development and progression remained unsolved. Recently, transcriptome-wide profiling approaches have uncovered a large family of long noncoding RNAs (lncRNAs). Larger than 200 nucleotides and with no apparent protein coding potential, lncRNAs could unveil a new set of players in AML development. Originally considered as dark matter, lncRNAs have critical roles to play in the different steps of gene expression and thus affect cellular homeostasis including proliferation, survival, differentiation, migration or genomic stability. Consequently, lncRNAs are found to be differentially expressed in tumors, notably in AML, and linked to the transformation of healthy cells into leukemic cells. In this review, we aim to summarize the knowledge concerning lncRNAs functions and implications in AML, with a particular emphasis on their prognostic and therapeutic potential.

Keywords: acute myeloid leukemia; biomarkers; long noncoding RNA.

Figure 1

Long Noncoding RNAs: a truly large and multifaced family. Nuclear lncRNAs are implicated in (A) Epigenetic regulations, leading to the recruitment of activator/repressor chromatin modifying complexes on their target promoters, (B) Transcriptional regulations, guiding or preventing the recruitment of transcription factors on the promoters of their targets or on other active chromatin sites, (C) Splicing regulations regulating recruitment of spliceosome partners. Cytoplasmic lncRNAs also affect post-transcriptional steps regulating (D) mRNA stability modulating degradation, positively or negatively or acting as (E) small regulatory RNA sponges. Finally, they regulate (F) mRNA translation. LncRNAs can also be (G) small peptide producers.

Figure 2

LncRNAs control cell survival and myeloid differentiation leading to AML development. Several examples of lncRNA-controlled pathways are illustrated in this picture, showing known lncRNA targets and how they are regulated.

Figure 3

LncRNAs in clinic: (A) lncRNA biomarkers. High throughput technologies are used to quantify lncRNAs and highlight their prognostic potential. LncRNAs are promising predictive biomarkers as their expressions can be highly tissue and/or cancer specific. Some of them are even present in biofluids allowing an easy and non-invasive detection method. (B) LncRNAs as a therapeutic tool. Highly cancer-specific, lncRNAs can be used as tools to selectively kill tumor cells. For example, a plasmid containing diphtheria toxin under the control of H19 regulatory sequences has been designed to selectively target tumor cells which overexpressed H19 compared to normal cells. Diphtheria toxin is massively produced and selectively kills H19-overexpressing tumor cells. (C) LncRNAs targeted cancer therapies. Oncogenic LncRNAs as target: silencing of its expression: (1) Small interfering RNA (siRNA) are double-stranded RNA oligonucleotides antisense and complementary to target lncRNA sequences. They induce degradation of their target by recruiting the RISC (RNA-induced silencing) complex. (2) An antisense oligonucleotide (ASO) is a single-stranded DNA oligonucleotide that is complementary to the target RNA and able to induce its degradation by recruiting RNase H. (3) Ribozymes (Ribonucleic acid Enzymes) are single-stranded RNA. By adopting specific conformations, they are able to bind RNA targets and catalyze their degradation. Oncogenic LncRNAs as target: silencing their activity: Small molecules are also able to hide partners’ interaction sites (DNA, RNA, proteins) to suppress their activities. (4) Aptamers are single stranded DNA folded into secondary and tertiary structures that can bind specific structural regions of the target lncRNAs. (5) Small molecule Inhibitors can also disrupt lncRNA interactions. Tumor suppressor lncRNAs as target: Rescue of its expression: It can be provided by common gene therapy strategies, packaging the whole transcript into viral or non-viral delivery tools. Future promising tool: (J) New Genome editing strategies such as CRISPR/Cas9 are developing very fast to knock-in/out lncRNA candidates.