Long non-coding RNA expression profile in cytogenetically normal acute myeloid leukemia identifies a distinct signature and a new biomarker in NPM1-mutated patients

Etienne de Clara (1) , Morgane Gourvest (1) , Hanjing Ma , François Vergez (1) , Marie Tosolini (1) , Sébastien Dejean (2) , Cécile Demur (1) , Eric Delabesse (1) , Christian Recher (3) , Christian Touriol (1) , Maria Paola Martelli (4) , Brunangelo Falini (4) , Pierre Brousset (1) , Marina Bousquet (1)

1 CRCT - Centre de Recherches en Cancérologie de Toulouse
2 IMT - Institut de Mathématiques de Toulouse UMR5219
3 Service Hématologie - IUCT-Oncopole [CHU Toulouse]
4 UNIPG - Università degli Studi di Perugia = University of Perugia

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.

Domaines: Cancer; Génomique, Transcriptomique et Protéomique [q-bio.GN]; Hématologie

Etienne de Clara, Morgane Gourvest, Hanjing Ma, François Vergez, Marie Tosolini, et al.. Long non-coding RNA expression profile in cytogenetically normal acute myeloid leukemia identifies a distinct signature and a new biomarker in NPM1-mutated patients. Haematologica, 2017, 102 (10), pp.1718 - 1726. ⟨10.3324/haematol.2017.171645⟩. ⟨hal-01890013⟩