Date Published: March 27, 2017
Publisher: Public Library of Science
Author(s): Mathieu Lajoie, Simon Drouin, Maxime Caron, Pascal St-Onge, Manon Ouimet, Romain Gioia, Marie-Hélène Lafond, Ramon Vidal, Chantal Richer, Karim Oualkacha, Arnaud Droit, Daniel Sinnett, Bin Shan.
Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is a heterogeneous disease involving many subtypes typically stratified using a combination of cytogenetic and molecular-based assays. These methods, although widely used, rely on the presence of known chromosomal translocations, which is a limiting factor. There is therefore a need for robust, sensitive, and specific molecular biomarkers unaffected by such limitations that would allow better risk stratification and consequently better clinical outcome. In this study we performed a transcriptome analysis of 56 pre-B cALL patients to identify expression signatures in different subtypes. In both protein-coding and long non-coding RNAs (lncRNA), we identified subtype-specific gene signatures distinguishing pre-B cALL subtypes, particularly in t(12;21) and hyperdiploid cases. The genes up-regulated in pre-B cALL subtypes were enriched in bivalent chromatin marks in their promoters. LncRNAs is a new and under-studied class of transcripts. The subtype-specific nature of lncRNAs suggests they may be suitable clinical biomarkers to guide risk stratification and targeted therapies in pre-B cALL patients.
Pre-B cell childhood acute lymphoblastic leukemia (pre-B cALL) is the most frequent pediatric cancer, representing ~25% of all cases. Prognosis is based on the absence or the presence of chromosomal rearrangements or gross aneuploidy [1,2]. High hyperdiploidy (HeH) cases, defined as having >50 chromosomes [3,4], and the t(12;21)[ETV6/RUNX1] rearrangement represent together nearly half of the chromosomal anomalies encountered in pre-B cALL and are associated with a favorable outcome [5,6]. Other subtypes, such as MLL-rearranged, t(1;19)[TCF3/PBX1], or t(9;22)[BCR/ABL1] are seen at much lower frequencies (<10%) and are associated with intermediate-to-poor outcomes [1,2]. Despite the availability of these molecular and chromosomal markers, accurate patient risk stratification is an ongoing challenge in cALL treatment. Indeed, karyotyping requires the observation of multiple cells undergoing mitosis, which are not always available or present in bone marrow or peripheral blood smears. Furthermore, current molecular approaches used in the detection of known chromosomal rearrangement yielding chimeric proteins, although highly sensitive, are not suitable for disease subtypes lacking these fusion products. Accurate patient stratification is the key to efficient, personalized pre-B cALL treatment. To date, childhood leukemia research has mainly focused on the expression deregulation of protein-coding genes that could be used as diagnostic and prognostics biomarkers. The human transcriptome comprises not only protein-coding mRNAs but also a large set of non-protein coding transcripts that have structural, regulatory or unknown functions . In this study, we performed a whole the transcriptome analysis to discriminate pre-B cALL subtypes using both the coding and non-coding landscapes. We observed significant differences in gene expression levels between subtypes indicating that gene expression pattern could potentially be used to stratify the patient in each pre-B ALL subtype. Several such studies had previously reported that protein-coding genes’ expression profile could discriminate subtypes [7,8,21]. Source: http://doi.org/10.1371/journal.pone.0174124