Research Abstracts Online
January - December 2011
University of Minnesota Twin Cities
College of Biological Sciences
of Genetics, Cell Biology, and Development
PI: Linda Baughn
Identification of Genetic Signatures Associated With Proteasome Inhibitor-Resistant Multiple Myeloma
Multiple myeloma (MM), the second most common hematopoietic malignancy, is an incurable plasma cell neoplasm representing approximately 2% of all cancer deaths. The proteasome inhibitor, Bortezomib (Bz), is widely used to treat multiple myeloma, and emerging next-generation proteasome inhibitors are being evaluated. However, due to the development of drug resistance, patients treated with Bz eventually relapse. Thus, the goal of this research is to decipher the genetic signatures that distinguish Bz-resistant from sensitive MM cells in order to predict Bz sensitivity and develop novel approaches to reverse Bz resistance. To this end, the researchers have utilized isogenic pairs of Bz resistant and sensitive MM lines derived from the genetically engineered iMycCα/Bcl-xl mouse model of plasma cell malignancy. The iMycCα/Bcl-xl mouse is a highly robust model that very closely resembles human myeloma based on gene expression profiling (GEP), chromosomal abnormalities and progression of disease and response to therapy validating the tremendous strength of this system. From their GEP analysis, the researchers observed an increased expression of Pax5, AID, and Bcl-6 and reduced expression of CD93 in Bz resistant lines compared to Bz sensitive lines suggesting that Bz resistance could be associated with a phenotype representing an earlier, germinal center-like stage of B cell differentiation.
The three aims of this research are: to characterize the B cell differentiation phenotypes of Bz sensitive and resistant mouse MM cells and determine how Bz treatment results in the formation of these phenotypes; to evaluate B cell differentiation phenotypes in human MM patients with good and poor prognosis; and to use a lentiviral-based approach to identify B cell differentiation proteins that can reverse Bz resistance. The researchers anticipate that they will identify B cell differentiation targets that represent a rational therapeutic approach to overcoming Bz resistance, including resistance to other next-generation proteasome inhibitors.
Brian Van Ness, Faculty Collaborator