WEHI PhD Completion Seminar hosted by Professor Daniel Gray

Mengxiao Luo

PhD Student – Gray Laboratory, Immunology division – Infection, Inflammation & Immunity Theme, WEHI

The impact of targeting BCL-2 pro-survival proteins on cell competition in leukemia

 

Davis Auditorium

Join via SLIDO enter code #WEHIphdcompletion

Including Q&A session

Followed by refreshments in Tapestry Lounge

The B-cell lymphoma-2 (BCL-2) family proteins are essential regulators of apoptotic cell death, maintaining the homeostasis of healthy lymphocytes but also promoting the aberrant survival of leukemias. The capacity to target this pathway and eliminate cancerous immune cells is exemplified by Venetoclax, the first small-molecule inhibitor of BCL-2 approved for the treatment of cancer. Although highly effective for certain haematological cancers, relapses remain a problem. Overcoming this problem by combining Venetoclax with other cancer therapies is now a major goal, yet there is still a need to understand the survival mechanisms of leukemic cells under BCL-2 inhibition to guide better strategies. Furthermore, there remains a poor understanding of its impact on the immune system homeostasis in vivo.

To address these knowledge gapes, we conducted high-dimensional mass cytometric profiling of serial samples from patients during early treatment with Venetoclax, and used diverse mouse models to gain mechanistic insights. These experiments led to the identification of a cytokine feedback loop and survival axis that blunts the effectiveness of Venetoclax. This work provides critical insights into the early responses of cancer cells to targeted therapies via homeostatic cytokines, informing new combinational strategies for more potent responses in cancer patients.

In a separate study, we investigated how defective cell competition can lead to acute lymphocytic leukemia in a mouse model and discovered a critical and counter-intuitive role for the pro-survival protein BCL-2 as a tumour-suppressor gene. Our findings underscore the dynamic and highly context-dependent nature of BCL-2 protein functions. Together, these discoveries highlight the need for a nuanced understanding of BCL-2’s role in cancer biology with consideration of the homeostatic and competitive responses within highly dynamic cell populations.

All welcome!