I have a longstanding interest in lymphoma biology dating back to the early 1990's when I worked as a post-doc in the laboratory of Dr. Robert Gallo at the National Cancer Institute after completing my medical oncology fellowship at the MD Anderson Cancer Center. About a decade ago, my lab identified a novel oncogene, MCT-1 from a human lymphoma cell line and demonstrated its capacity to transform immortalized cells as well as to alter their cell cycle kinetics. MCT-1 interacts with the density-regulated protein (DENR/DRP), an SUI1 domain-containing domain. The SUI1 domain is involved in recognition of the initiation codon by the eIF2-GTP-Met-tRNAi ternary complex. MCT-1 contains a PsuedoUridine synthase and Archaeosine transglycosylase (PUA) domain, which is a recently described RNA binding domain. A paradigm for how MCT-1 transforms cells has been proposed in which MCT-1 bound to DENR binds to the cap complex resulting in enhanced translation initiation of cancer-related mRNAs by scanning and recognition of the initiation codon. Employing translational profiling methodology, we were able to demonstrate that MCT-1 was able to upregulate the translation of a subset of cancer-related mRNAs involved in cell growth regulation, proliferation and apoptosis.

The abnormal regulation of protein synthesis in lymphoma cells has the potential to be exploited for cancer therapy. Towards this end, we were able to show that when MCT-1 function was repressed using a dominant-negative mutant approach the translational profile of tumor cells was altered and the malignant phenotype was attenuated. Recently, we demonstrated that the vast majority of primary DLBCL (85%) have elevated protein levels of MCT-1. The current challenge is to identify the complete repertoire of translated mRNAs regulated by MCT-1. Through our ongoing collaboration with Zhenqiu Liu from the Division of Biostatistics, we hope to characterize the genetic networks and processes employing comprehensive translational profiling of DLBCL cells. These important experiments will help us to understand how perturbation of MCT-1-regulated genes contributes to lymphomagenesis.