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.Cancers 2019, 11, 1638 2 of 24 highlighted recently but are steadily on the increase. Herein, we review the current understanding of lncRNAs deregulation in AML with an emphasis on their putative therapeutic potential. Background on lncRNAsArbitrary defined as transcripts of over 200 nucleotides without coding potential, lncRNAs were originally considered as dark matter due to their low expression and poor conservation across species compared to their messenger RNAs counterparts [13][14][15][16]. However, lncRNAs are tightly controlled and exhibit higher tissue and development specific expression than proteins-including lineage determining transcription factors-which support their biological functions [17,18]. Mostly transcribed by RNA Polymerase II, lncRNAs mimic mRNAs in their biogenesis and regulation: most of them are capped, polyadenylated, and spliced via canonical genomic splice site motifs [16]. Their transcription is also regulated by chromatin modifying complexes and specific transcription factors. Nevertheless, we also observe diversity with some non-polyadenylated or unspliced lncRNAs, lncRNAs transcribed by RNA Polymerase III [19,20] and snoRNA-related lncRNAs (sno-lncRNAs) expressed from introns via the snoRNP machinery [21].Because of their heterogeneity, much debate remains to find the best classification system for lncRNAs that are currently defined according to their genomic location. Indeed, lncRNAs can be divided into sense [22] or antisense [23] lncRNAs when the lncRNA sequence overlaps with the sense or antisense strand of a protein coding gene, respectively. They can also be defined as intronic lncRNA when it is derived entirely from an intron of another gene, as bidirectional when the transcription of the lncRNA is i...

Long non-coding RNAs are defined as transcripts larger than 200 nucleotides but without protein-coding potential. There is growing evidence of the important role of long non-coding RNAs in cancer initiation, development and progression. In this study, we sought to evaluate the long non-coding RNA expression profile of patients with cytogenetically normal acute myeloid leukemia (AML). RNA-sequencing of 40 cytogenetically normal AML patients allowed us to quantify 11,036 long non-coding RNAs. Among these, more than 8000 were previously undescribed long non-coding RNAs. Using unsupervised analysis, we observed a specific long non-coding RNA expression profile dependent on the mutational status of the NPM1 gene. Statistical analysis allowed us to identify a minimal set of 12 long non-coding RNAs capable of discriminating NPM1-mutated from NPM1-wild-type patients. These results were validated by qRT-PCR on an independent cohort composed of 134 cytogenetically normal AML patients. Furthermore, we have identified one putative biomarker, the long non-coding RNA XLOC_109948 whose expression pattern predicts clinical outcome. Interestingly, low XLOC_109948 expression indicates a good prognosis especially for NPM1-mutated patients. Transient transfection of GapmeR against XLOC_109948 in NPM1-mutated OCI-AML3 cell line treated with Ara-C or ATRA enhances apoptosis suggesting XLOC_109948 plays a role in drug sensitivity. This study improves our knowledge of the long non-coding RNA transcriptome in cytogenetically normal AML patients. We observed a distinct long non-coding RNA expression profile in patients with the NPM1 mutation. The newly identified XLOC_109948 long non-coding RNA emerged as a strong prognostic factor able to better stratify NPM1-mutated patients.