Description:

The Department of Biochemistry and Molecular Genetics Departmental Seminar Series presents:

Markus Müschen, MD, PhD
Professor, Department of Laboratory Medicine
Program Co-Leader, Hematopoietic Malignancies Program, UCSF Helen Diller Family Comprehensive Cancer Center
University of California, San Francisco

Targeted therapy of cancer typically focuses on inhibitors (e.g. tyrosine kinase inhibitors, TKI) that suppress oncogenic signaling below a minimum threshold required for survival and proliferation of cancer cells. Acute lymphoblastic leukemia (ALL) originates from pre-B cells, which unlike other cell types are under intense selective pressure. The vast majority of newly generated pre-B cells die at central tolerance checkpoints for removal of autoreactive clones. Pre-B cells expressing autoreactive immunoglobulin m heavy chains bind ubiquitous self-antigen, resulting in excessive signaling strength above a maximum permissive threshold. Activation of B cell tolerance checkpoints induces cell death and clearance of autoreactive clones from the repertoire. A series of recent findings demonstrated that, despite malignant transformation, central B tolerance checkpoints are fully functional in human ALL. We propose that targeted engagement of B cell tolerance checkpoints, e.g. through short transient hyperactivation of (pre-) B cell receptor signaling, represents a previously unrecognized therapeutic opportunity to overcome conventional mechanisms of drug-resistance in human ALL and other B cell malignancies.