Final Report Summary - DECODER (DECiphering the role of long non COding Rna in cancer)
Coding Genes represent less than 2% of our genome. However about 80% of our genome is biochemically functional and 70% is actively transcribed, with long non coding RNAs (lncRNAs) and pseudogenes largely outnumbering the amount of coding genes. In this project we started to analyze the biological significance of lncRNAs in cancer using Acute Promyelocytic Leukemia (APL) as a model system. APL accounts for more than 10% of all acute myeloid leukemias and is characterized by reciprocal translocations involving the retinoic acid alpha-receptor (RARA) and the promyelocytic gene (PML). PML-RARA is a potent epigenetic modifier able to bind specific genetic loci and to consequently arrest the differentiation program at the promyelocitic stage of myeloid maturation. Treatment with pharmacological doses of Retinoic Acid can result in APL differentiation, by modulating the expression of thousands of genetic loci including many lncRNAs. Here we investigated the biogenesis of lncRNA candidates and identified regulatory regions involved in their transcription. Interestingly, we observed that these regions are conserved and bound by transcriptional factors involved in normal myeloid commitment and differentiation. Indeed, although lncRNAs are poorly conserved, DNA motifs and transcriptional factors involved in their regulation are generally conserved across evolution. We identified a lncRNAs family, including members which are significantly upregulated upon Retinoic Acid treatment of APL cells and during normal myelopoiesis. Thus these lncRNAs are likely to be an integral part of the genetic program activated during myeloid differentiation. Overexpressing one of the family members had a citostatic effect on leukemic cells. The same family member was upregulated in primary AML samples following ATRA treatment. Thus this lncRNA may represent a valuable biomarker to evaluate response to therapy in leukemia. Deconstructing the complexity of the non-coding genome and studying the relationship between the coding and non-coding component of DNA may represent the basis to identify novel relevant pathways and to ultimately develop new therapeutic strategies in cancer.