Long noncoding RNAs are defined as transcripts larger than 200 nucleotides but without protein-coding potential. Cumulative evidence points towards an important role of long noncoding RNAs in cancer initiation, development and progression. In this study researchers from the Cancer Research Center of Toulouse sought to evaluate the long noncoding RNA expression profile of patients with cytogenetically normal acute myeloid leukemia. RNA-sequencing of forty cytogenetically normal acute myeloid leukemia patients allowed us to quantify 11036 long noncoding RNAs. Among them more than 8000 were previously-undescribed long noncoding RNAs. Using unsupervised analysis they observed a specific long noncoding RNA expression profile dependent on the mutational status of NPM1 gene. Statistical analysis allowed us to identify a minimal set of 12 long noncoding 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 acute myeloid leukemia patients. Furthermore, the researchers have identified one putative biomarker, the long noncoding 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 a role of XLOC_109948 in drug sensitivity.
Specific lncRNA expression profile for NPM1-mutated AML patients with normal cytogenetics
A Unsupervised hierarchical clustering analysis of 40 patients with CN-AML (Cohort 1: NPM1+, n=14; NPM1wt, n=26) using 11065 lncRNAs (RNA-seq data). B Hierarchical clustering and associated heatmap of Fluidigm data from the first cohort of CN-AML patients (n=40) with 31 lncRNAs differentially-expressed between NPM1-mutated (n=14) and NPM1-wild type patients (n=26). C Hierarchical clustering and associated heatmap of Fluidigm data from the second cohort of 134 CN-AML patients (NPM1-mutated (n=80) and NPM1-wild type (n=54)). The heatmap depicts high expression (red, +1) and low expression (blue, −1).
This study provides a better knowledge of the long noncoding RNA transcriptome in cytogenetically normal acute myeloid leukemia patients. The researchers observed a distinct long noncoding RNA expression profile in patients with the NPM1 mutation. The newly identified XLOC_109948 long noncoding RNA emerged as a strong prognostic factor able to better stratify NPM1-mutated patients.