BEAT IT
BCL2 Network Adaptations in B Cell Transformation
FWF - FORSCHUNGSGRUPPE (FG)
The conceptual understanding of how cancer arises has been influenced profoundly by the recognition that healthy tissues can contain tumor-associated mutations or chromosomal abnormalities without progressing to cancer. If these abnormalities in cells and their progeny do not inevitably cause cancer, what does? One hallmark of malignant transformation is evasion from programmed cell death, most notably mitochondrial apoptosis controlled by BCL2 family proteins. While synergies between genomic alterations and impaired apoptosis in tumors were noted 30 years ago, little is known on the molecular underpinning of BCL2 network reprogramming in genetically perturbed and transforming cells.
Blood cancer has been at the forefront of progress in studying cancer etiology and therapy. Yet, the early processes enabling blood cell transformation remain to be fully uncovered. The BEAT IT project funded by the Austrian Science Fund (FWF) aims to decode how epigenetic, karyotypic, or genetic perturbation, either alone or in combination with aberrant oncogene activity, rewire the BCL2 network to nudge normal blood cells into malignancy (see also Projects). Understanding the molecular dependencies that arise as a consequence of BCL2 network reprogramming will shine light on vulnerabilities that can be therapeutically exploited to prevent cancer onset or progression.
We will introduce (1) epigenetic, (2) karyotypic, or (3) mutational perturbations, either alone or in combination with aberrant expression of the MYC oncoprotein, into primary mouse B cells. In a collaborative effort, we will scrutinize the global impact of these perturbations on the transcriptome, genome, karyotype, and chromatin accessibility. The resulting data sets will be combined with targeted analysis of BCL2 network rewiring to create a “road map” of B cell survival during transformation.
Developing a road map to the molecular rewiring of cell death networks in B cell transformation. The BEAT IT consortium will collaborate to understand the molecular mechanisms securing the survival of early B cell progenitors that experience epigenetic, karyotypic or genetic abberations.
Induction of apoptosis is at the core of current cancer therapies and direct targeting of the BCL2 network has reached the clinics. Despite the wealth of knowledge on apoptosis, we do lack an understanding how transforming cells escape extinction. We seek to understand the cell death dynamics that unfolds upon selective introduction of genomic perturbations in mouse B cells, and provide proof of concept that this knowledge can be used to promote healthy ageing.
Intertwining four research groups (see also Team), this consortium will condense individual expertise in preclinical blood cancer models, apoptosis, cell cycle control and mitochondrial dynamics, advanced imaging, and large NGS-data processing. This strategy will create synergies across multiple life-science disciplines at the Medical University of Innsbruck and the University of Innsbruck, increasing their international visibility and competitiveness.
