Project 3: Defining the biologic role and therapeutic implications of lncRNA in multiple myeloma

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Project Summary – Project 3 Dana-Farber Cancer Institute Our longstanding focus has been to understand the multiple myeloma (MM)-bone marrow stromal cell interaction. We have utilized integrated genomic and epigenomic analysis and our in vitro and in vivo models of MM cell in the bone marrow (BM) milieu to identify molecular targets and pathways supporting myeloma cell growth, survival, and drug resistance, and implement effective molecularly-based therapies with dramatic effects on the survival of MM patients. During the current funding period, we identified and validated gene regulatory networks and feed-forward loops controlling gene transcription and driving disease behavior and then evaluated targeted agents. In the process we identified the noncoding RNA (lncRNA) networks in MM. One of the emerging areas of research has been the recent advances highlighting the functional significance of lncRNAs) that span > 80% of the human genome. These RNA molecules control a variety of cellular and molecular functions via mechanisms that are yet not well described. We have previously described the aberrant lncRNA landscape in MM and reported the significant role of aberrant lncRNAs as an independent risk predictor for clinical outcome, providing the rationale to further investigate biological and molecular activity of lncRNAs in MM. We hypothesize that dysregulated lncRNAs significantly impact the pathobiology of MM by their ability to control multiple genes, with the potential to serve as therapeutic targets. In this project, our robust human MM model systems will be used to stringently validate the role of novel lncRNAs (Sp. Aim 1) identified to be of biologic/prognostic significance; and develop single and combination therapies directed against these clinically and biologically relevant novel lncRNAs (Sp. Aim 2). Leveraging our genomic and transcriptomic data, the proposed studies will define the functional landscape of lncRNAs in MM and their impact on the disease pathobiology, with the potential of developing novel translational therapies for the treatment of MM patients.