The Role and Regulation of Monocarboxylate Transporters 1 and 4 in Epstein-Barr Virus-mediated B Lymphocyte Tumorigenesis

爱泼斯坦-巴尔病毒（EBV）是一种普遍存在的病毒，在初次感染时建立潜伏期，但可以劫持宿主

Epstein-Barr Virus (EBV) is a ubiquitous virus that establishes latency upon primary infection, but can hijack host metabolic pathways to promote tumorigenesis in immune-compromised hosts. The goal of this proposal is to determine how EBV regulation of lactate export through MCT1 and MCT4, can promote B cell immortalization, and be exploited for therapeutic benefit. My central hypothesis is that EBV temporally upregulates MCT1/4 to promote B cell growth by mitigating the increased intracellular lactate burden accrued during immortalization. This hypothesis is based on the rationale that lactate export is crucial for preventing intracellular acidification, which can be detrimental to cell growth. Our laboratory has published that during EBV immortalization of B cells in vitro, glycolysis is significantly upregulated. We also observed increased extracellular acidification rates (ECAR), which is largely a reflection of lactate excreted during glycolysis. However, the role of lactate export in EBV-mediated B cell immortalization has never been explored. Lactate export is regulated by the plasma membrane-resident proteins monocarboxylate transporters 1 and 4 (MCT1/4), which have been associated with tumor development and progression in various cancers. We have observed a significant increase in extracellular and intracellular lactate levels during the course of EBV B cell immortalization. In vitro, EBV immortalization of B cells into indefinitely proliferating lymphoblastoid cell lines(LCLs) induces two distinct latency programs, Latency IIb and Latency III. LCLs express the Latency III growth program, where all six EBV Nuclear Antigens (EBNA- LP, 1, 2, 3A, 3B, and 3C) and two Latent Membrane Proteins (LMP1 and LMP2) are present. This gene expression program mimics that of many EBV-associated B-lymphoid cancers, making LCLs a suitable model for studying mechanisms underlying tumorigenesis. Shortly after infection and prior to Latency III establishment in LCLs, early EBV-infected B cells express the Latency IIb growth program, where only the viral EBNAs are expressed. We have observed that MCT1 is upregulated during Latency IIb, and MCT4 during Latency III, suggesting that MCT1/4-mediated lactate export might be important for EBV-driven B cell immortalization. I plan to test this hypothesis by pursuing the following specific aims: 1.) Determining the viral mechanism for MCT4 upregulation and role in MCT1 inhibitor resistance 2.) Uncovering underlying changes that promote growth arrest in dual MCT1/4 inhibition 3.) Exploring dual MCT1/4 inhibition as a therapeutic strategy in virus-associated lymphomas.