Grant: Project Grant

Diffuse large B-cell lymphoma (DLBCL) is the most commonly diagnosed type of white blood cell cancer worldwide. While modern treatments for DLBCL are effective, they do not cure ~40% of patients. Outcomes for these patients remain very poor. It has long been recognized that DLBCL is actually a collection of different cancers, bundled together by their appearance, the proteins they carry, and how they behave clinically. We developed a system to separate DLBCL into groups ("molecular subtypes") based on patterns of genetic mutations within the tumour cells. This system helps classify patients based on how their tumours are "wired", potentially allowing us to provide treatments tailored to each tumour type, thereby increasing effectiveness and reducing side effects. However, this system is not complete and ~40% of patients still cannot be placed in any specific group. Recently, we discovered the existence of populations of pre-cancerous white blood cells ("common precursor cells" [CPCs]) that act as the "seeds" for DLBCL tumours. Our previous work suggests that different types of CPCs have different genetic mutations and give rise to the different molecular subtypes of DLBCL. In this proposal, we will apply DNA sequencing technologies to human lymphomas to fully characterise the patterns of mutations in CPCs. We will use mouse models of lymphoma to track the different pathways that pre-cancerous CPCs take to become full-blown cancer. We anticipate that these experiments will result in a refined, more complete system for matching patients' tumours to effective treatment plans. The knowledge generated will also be foundational to developing strategies to detect and target these CPCs to stop them in their tracks, before they can give rise to DLBCL.