Uncovering new tumor progression genes in B cell lymphoma using insertional mutagenesis

Our lab studies the signaling and genetic events leading to B cell malignancy, especially in the context of the plasma stage of B cell development. A unique transgenic mouse model of plasma cell neoplasia engineered to mimic several features of human multiple myeloma provides the basis for these experiments. This mouse contains an extra copy of the c-Myc gene added within the immunoglobin gene. The potent Myc oncogene is thus expressed at elevated levels in the antibody (immunoglobulin) producing plasma cell, causing a spontaneous malignant transformation. Cancer in this mouse model exhibits a late onset of B cell lymphoma similar to onset in humans and provides a crucial test-bed for studying the disease.

Insertional mutagenesis is a gene discovery tool whereby a virus or transposon inserts a promoter or “on signal” into the promoter-proximal region of an unknown but traceable gene. Our mouse model is subjected to insertional mutagenesis by two systems: the Moloney Murine Leukemia Virus (M-MuLV) and the Sleeping Beauty retrotransposon. Insertional mutagenesis favors the activation of oncogenes by increasing their expression similar to the types of genetic lesions occurring in human cancers. Bioinformatic and statistical approaches help to separate driver genes from passenger genes. Passenger mutations are those that are believed to be uninvolved with the genetic events that lead to tumor development, whereas a very few genes hold a principle or “driver” role in the process. We aim to generate and test new driver genes that support and cause progression of plasma cell neoplasia. This work is centered on offering both novel therapeutic targets to treat multiple myeloma as well as signatures of the disease, so called “biomarkers,” that allow clinicians to detect these types of blood cell cancers early in their development.

Tompkins VS, Han SS, Olivier A, Syrbu S, Bair T, Button A, Jacobus L, Wang Z, Lifton S, Raychaudhuri P, Morse HC 3rd, Weiner G, Link B, Smith BJ, Janz S. Identification of candidate B-lymphoma genes by cross-species gene expression profiling. PLoS One. 2013 Oct 9;8(10):e76889. doi: 10.1371/journal.pone.0076889. eCollection 2013. PubMed PMID: 24130802; PubMed Central PMCID: PMC3793908.