Exploring the Metabolic Vulnerabilities of Multiple Myeloma: The Role of MYC in Glutamine Metabolism
Multiple Myeloma (MM) is a malignancy of terminally differentiated B cells characterized by the accumulation of clonal plasma cells in the bone marrow. The proto-oncogene MYC is often overexpressed or translocated in MM and is critical for its transformation from monoclonal gammopathy of undetermined significance (MGUS) to smoldering and overt MM. Furthermore, MYC is associated with other known MM oncogenes, such as IRF4 and KRAS that maintain expression and stability of MYC, respectively.
In addition, cancer cells undergo extensive metabolic reprogramming, and MYC plays a crucial role in orchestrating these metabolic changes. One of the critical areas impacted by MYC overexpression is glutamine metabolism, which is important to fulfill the energetic demands of cancer cells, as well as supply biosynthetic precursors for growth and proliferation. To date, there are no approved therapies to directly target MYC, highlighting the need to characterize the regulation and downstream functions of MYC, including its role in the metabolic features of MM cells.
We analyzed RNA sequencing datasets from untreated MM patients' plasma cells, stratified by C-MYC mRNA expression. MM cell lines with doxycycline-inducible MYC overexpression were generated to assess MYC's effects on metabolic features and signaling outputs.
Inducible overexpression of MYC resulted in cell death MM cell lines, even in cell lines already harboring MYC aberrations. MYC-driven cell death could be partially rescued by the pan-caspase inhibitor QVD, suggesting that MYC overexpression activates caspase-dependent apoptosis of MM cells. These results indicate that in spite of MYC aberrations, an upper limit of MYC expression exists in MM.
Differential gene expression analysis of MM patients stratified based on C-MYC mRNA expression (upper quartile versus lowest quartile) indicates that the expression of several rate-limiting genes involved in de novo nucleotide synthesis are positively associated with C-MYC expression. In agreement, inducible MYC overexpression in MM cell lines resulted in a modest but significant increase in S phase engagement, requiring an increased demand on nucleotide biosynthesis.
MM cell lines showed differential sensitivity to glutamine deprivation, exacerbated by MYC overexpression. Glucose deprivation had less impact on cell survival compared to glutamine deprivation.While single nucleoside supplementation was ineffective, mixed nucleoside supplements partially restored viability in glutamine-deprived cells.
Our findings highlight the critical role of MYC in regulating glutamine metabolism and nucleotide biosynthesis in MM cells, revealing a potential therapeutic vulnerability. The differential sensitivity to glutamine deprivation and the partial rescue by mixed nucleoside supplementation suggests that targeting glutamine metabolism, particularly in MYC-overexpressing MM cells, may offer a promising strategy for MM treatment. Further investigation into the mechanisms underlying this metabolic dependency could lead to the development of novel, targeted therapies for MM.