University of Florida
Project Term: October 1, 2021 - September 30, 2024
The goal of my research is to characterize the role of the cellular metabolic regulator AK2 in multiple myeloma (MM) pathogenesis and therapy resistance. A series of molecular, biochemical, and functional assays will be performed using laboratory models to define the basis of MM cell dependence on AK2 and elucidate its role in MM progression and drug resistance. This work will highlight novel metabolic vulnerabilities in MM that can be targeted to further enhance therapeutic outcomes.
Multiple myeloma (MM) is the second most common blood cancer. It arises from plasma cells, the bone marrow cells that produce antibodies to fight infections. Different subtypes of MM are driven by diverse genetic abnormalities and are associated with varying patient survival rates. A cellular protein called NSD2 that is known to chemically modify chromatin, the DNA-protein complex containing genetic information, can drive MM development when overproduced. Overproduction of NSD2 is found in 15% of MM patients and is associated with poor patient survival. Identification of cellular vulnerabilities that are specific to MM in general, or to particular subtypes of this disease, is important for developing novel therapies. My previous research revealed that survival of MM cells, especially those over producing NSD2, is selectively dependent on a cellular enzyme called adenylate kinase 2 (AK2). This finding suggests that inhibiting the function of AK2 can be used to treat MM. I am now proposing a series of experiments to understand why MM cells with high NSD2 levels are more susceptible to AK2 disruption. I further propose to thoroughly investigate the function of AK2 in cultured MM cells as well as MM mouse models and to elucidate, at the molecular level, why AK2 is essential for MM cell survival. Finally, I will investigate the role of AK2 in resistance to existing MM therapies using laboratory models with the aim of finding strategies to reverse such resistance. To achieve these goals, I will use state-of-the-art molecular biology tools such as “CRISPR” gene-editing, cytometry, proteomic, metabolomic, and gene expression profiling as well as next-generation DNA sequencing. Based on what is known about AK2 and my preliminary studies, I anticipate that MM cells rely on AK2 to maintain the balance of nucleotides, the building blocks of DNA, in MM cells. Also, AK2 could be required to lower cellular stress originating from increased antibody production, a characteristic feature of MM cells. Given the limited treatment options and high relapse rates of MM patients, especially those with high NSD2 levels, this research may have important clinical implications.