Bcl-2 family members in microenvironmental support in Chronic Lymphocytic Leukemia

• Applicant: Privatdozent Dr. Alexander Egle
• Subject Area: Hematology, Oncology ; Cell Biology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 232935877

Chronic lymphocytic leukemia (CLL) is a conventionally incurable disease with increasing prevalence and is characterized by a high degree of heterogeneity, both on the level of prognosis of individual patients as well as on that of underlying biology. Recent insights into the biology and genetic wiring of CLL paint a very diverse picture with a majority of genetic aberrations present in only small minorities of patients and increasing evidence that microenvironmental inputs are at least equally critical drivers of CLL progression. It may thus be more attractive for the treatment of CLL to find largely unmutated pathways or cellular rheostats, deriving their signals from microenvironmental interactions, essential for CLL proliferation and survival. In this respect, the Bcl-2 family of proteins represents an optimal candidate target. While there is some knowledge of deregulation of individual Bcl-2 family members in CLL, the family is still poorly studied in larger cohorts and the interplay with the emerging complex landscape of genetic lesions is unknown. Also Bcl-2 family regulation via microenvironmental stimuli has not been addressed satisfactorily. In the first funding period, we established a comprehensive library of CLL mice with genetic modifications of the Bcl-2 family. Our ex vivo observations suggest that Bcl-2 family members are critical regulators of cell death in response to deprivation from microenvironmental inputs in CLL and this is supported by transplantation results, indicating essential roles of Bcl-2 family proteins for clonogenicity in vivo. In addition, we observed unknown and specific resistance mechanisms aiginst novel drugs. In parallel analyses of primary human CLL, we observed unsupervised clustering of functional subsets in the Bcl-2 family, with clusters being able to predict CLL prognosis. This demonstrates that Bcl-2 family composition is significantly associated with patient fate. The primary goal of this proposal is, thus, to overcome the current lack of systematic and relevantly complete information on Bcl-2 family gene and protein expression in CLL in correlation to relevant biological endpoints in vivo and in vitro and to better characterize the interplay of microenvironmental and genetic factors in CLL. This will be achieved by complete characterization of a large clinical cohort on all relevant levels to create a model for Bcl-2 family controlled life/death decisions in CLL. Murine models will be used to establish specific roles for Bcl-2 family proteins in microenvironmental interactions and in cell cycle associated cell death. The overall goal of the program is to improve our knowledge of the role of Bcl-2 family preoteins within complex microenvironmental and genetic interactions in order to predict optimal treatment combinations for the elimination of CLL in clinical contexts. All aims include critical collaboration within the project group.

• DFG Programme: Research Units
• Subproject of: FOR 2036: New Insights into Bcl-2 Family Interactions: From Biophysics to Function
• International Connection: Austria
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)