Defining the Biologic and Therapeutic Significance of the Novel Long Noncoding RNA MYND in Multiple Myeloma
Dana-Farber Cancer Institute
Project Term: July 1, 2022 - June 30, 2024
Long non-protein coding RNAs (lncRNAs) are fundamental for proper cell function, but their purpose is poorly understood in multiple myeloma. To systematically identify myeloma-promoting lncRNAs, we integrated gene expression profiling of myeloma patients with high-throughput loss-of-function studies in cell lines. Moreover, we optimized strategies to antagonize myeloma-promoting lncRNAs, thus paving the way to developing lncRNA inhibitors as the next generation of therapy.
Multiple myeloma (MM) is a cancer of plasma cells that accounts for about 10% of hematologic malignancies. Despite a broad portfolio of therapeutic agents, MM patients frequently suffer disease relapse and succumb to MM. Therefore, there is an unmet medical need for more effective therapies. Long non-protein coding RNAs (lncRNAs) are strands of RNA that perform critical roles within the cell, regulating many biological processes such as cell proliferation, differentiation, and apoptosis. Their genes are remarkably abundant in the human genome, outnumbering protein-coding genes. However, the roles of lncRNAs in human cancers are still poorly understood. In previous studies, we found that the abundance of particular lncRNAs was different between MM cells and normal plasma cells and that this abundance predicted the clinical outcome of MM patients. We developed strategies for identifying these critical MM-promoting lncRNAs, for understanding their mode of action and interaction with proteins and DNA, and for therapeutically targeting them in our mouse models of MM. Specifically, we adapted CRISPR technologies to conduct the most extensive search for tumor-promoting lncRNAs in any disease context and found more than 300 lncRNAs that MM cells depend on. We identified and validated the novel lncRNA MYND1, which is selectively expressed in MM cells and correlates with a more aggressive disease. Thus, we believe that lncRNA MYND1 is an attractive therapeutic target. In this proposal, we will investigate what MYND1 does in MM cells and how best to stop it in mouse models of MM. Our study will provide the basis for clinical trials of MYND1 inhibitors in MM. Moreover, with more than 300 identified lncRNAs, our study will also pave the way for future research on more lncRNAs in MM. Because lncRNAs can be easily and specifically degraded, unlike many proteins, we believe that lncRNAs constitute the next-generation of target molecules in MM therapy, providing effective and safe therapies for patients.