Understanding resistance towards venetoclax in lymphoma: physiology of genetic alterations in BTG1 and BCL2 (A06)

• Subject Area: Hematology, Oncology ; Cell Biology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 455784452

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.

• DFG Programme: Collaborative Research Centres
• Subproject of: SFB 1530: Elucidation and targeting of pathogenic mechanisms in B cell malignancies
• Applicant Institution: Universität zu Köln
• Project Heads: Dr. Lukas Frenzel; Professorin Dr. Ana Jesús Garcia Sáez