Dr. Alexandre Orthwein
Assistant Professor - Department of Oncology
Associate Member - Department of Medicine, Division of Experimental Medicine
Genetic diversity is crucial for B-cells to generate a large repertoire of antibodies capable of recognizing and eliminating the infinite spectrum of pathogens. This process relies mainly on the generation of cytotoxic DNA lesions, in particular DNA double-strand breaks (DSBs), which are predominantly targeted to the Immunoglobulin/antibody genes during B-cell development. Successful DSB repair results in antibody diversification and the establishment of a functional immune response. Inversely, improper repair can result in immunodeficiency syndromes characterized by recurrent infections. Approximately 29,000 Canadians suffer from primary immunodeficiency syndromes and about 70% of them are undiagnosed. Off-targets DSBs can also lead to chromosomal translocations, which fuel B-cell malignancies, including lymphoma, leukemia and multiple myeloma. These hematological malignancies represent the fourth most common type of cancer in Canada and despite considerable therapeutic advances most of the patients affected by aggressive hematological cancer are incurable.
My laboratory aims to understand how DSBs are repaired in B-cells to elicit a protective immunity while limiting B-cell carcinogenesis. My previous work has identified novel genes involved in DSB repair in B-cells and deciphered the tight link between cell cycle progression and DNA repair. Still, very little is known about how DSBs are controlled in B-cells during an infection. The overall goals of my laboratory is to (1) understand how DNA repair pathways are regulated in B-cells to favor genome stability and genetic diversity, (2) decipher the full spectrum of genes involved in the maintenance of genome stability in B-cells, (3) determine the mechanisms by which B-cells can become malignant upon induction of DSBs.
1. Identification of novel DNA repair factors during antibody diversification.
2. Identification of novel targets for the treatment of multiple myeloma.