Mammalian genomes are pervasively transcribed, but only a fraction of the transcribed RNAs appears to encode for proteins. Among the non-coding component of the transcriptome, long intergenic non-coding RNAs (lincRNAs) have recently been the subject of intense investigation due to their potential roles in cell differentiation, development, and disease. Although several lincRNAs have been proposed to play a role in the pathogenesis of human cancers, definitive experimental evidence is still missing and our understanding of the precise biological functions and modality of action of the vast majority of them is minimal or absent. Here we propose to investigate the potential roles of lincRNAs in the pathogenesis of Myc-driven B cell lymphomas. Our central hypothesis is that a subset of lincRNAs possesses oncogenic or tumor suppressive properties and that these lincRNAs contribute to lymphomagenesis. To test this hypothesis we are proposing a multidisciplinary approach that consists in a first high-throughput phase in which we aim to identify lincRNAs that are de-regulated during Myc-driven lymphomagenesis. Next, this set of lincRNAs will be subjected to in vitro and in vivo functional screens to identify those that can accelerate or impai tumor progression. Finally, the most promising candidates will be investigated through loss of function and gain of function experiments in genetically engineered mice. Our ultimate goals are to define the roles of these lincRNAs in tumorigenesis, determine their physiologic functions, and identify their mechanisms of action. We predict that the successful completion of the experiments described in this proposal will provide important insights into the biology of this important class of non-coding RNAs and will define their potential roles in tumorigenesis.
In this grant application, we propose to study the biological functions of a class of non-coding RNAs called lincRNAs. We propose a multidisciplinary approach aimed at identifying lincRNAs that are involved in the pathogenesis of human cancers and in particular Myc-driven B cell lymphomas. Our goals are to identify novel oncogenic and tumor-suppressive lincRNAs, to define their physiologic functions and to determine how their deregulation contributes to tumor formation. As such, the studies we propose have the potential to significantly impact public health and could pave the way for novel anticancer strategies and for the identification of novel diagnostic and prognostic markers.
