The BCL2 inhibitor venetoclax (VEN) has shown impressive clinical activity in several hematologic malignancies. However, the mechanisms of resistance to VEN are complex and not fully understood. Recently, we found that de-novo BTG1 mutations occur in CLL patients with acquired resistance to VEN and subsequent Richter transformation. BTG1 mutations are also found in DLBCL and r/r FL and associated with poor prognosis. Therefore, we will investigate the functional role of the BTG1 gene in high-risk CLL and DLBCL mouse models and VEN resistance. Our preliminary data from leukemic B cells with Btg1 knockout show deregulation of central BCL2 family members, such as BCL2, BAX or PUMA. Since the quantitative composition and mutations of BCL2 proteins at the mitochondrial membrane may contribute to resistance towards VEN, we will investigate the detailed composition of BCL2 complexes in lymphoma models and cells with VEN resistance.
PRINCIPAL INVESTIGATOR
Institute for Genetics
CECAD - Cluster of Excellence at the University of Cologne
Joseph-Stelzmann-Straße 26
50931 Cologne
Apoptosis-Signaling and Therapy Resistance Group
Department I of Internal Medicine
University Hospital of Cologne
Kerpener Straße 62
50937 Cologne
Project Interactions
-
B01
LYN kinase as a key regulator in the microenvironmental niche of B cell lymphoid tumors
Prof. Dr. med. Michael Hallek, Dr. rer. nat. Phuong-Hien Nguyen -
A04
Role of apoptotic caspases in lymphomagenesis
Prof. Dr. rer. nat. Hamid Kashkar -
C04
Modeling the clonal evolution of high-risk CLL
Prof. Dr. rer. nat. Martin Peifer, Dr. med. Kirsten Fischer