BCL2 Network Adaptations in B Cell Transformation

The process of how a normal, healthy cell becomes a cancer cell is largely unknown. Virtually all tumor types carry aberrations in their genetic code, or DNA, when compared to healthy cells of the same type. Such DNA aberrations, mostly mutations, chromosomal abnormalities or altered methylation, are thought to direct the fate of the tumor cells in early phases of tumor development. In recent years however, the understanding of how tumors arise has been influenced by the recognition that healthy cells can carry aberrations in their DNA without progressing to cancer. This begs the question: if these abnormalities in the DNA of a cell or its progeny do not cause tumors, what does? To address this fundamental, our BEAT IT team will focus its efforts on assessing how blood cells adapt over time to cope with the DNA aberrations they carry. Starting from a group of blood cells, termed B lymphocytes, the BEAT IT team will interrogate the impact of cancer-associated DNA aberrations on B lymphocyte biology. One hallmark of cell transformation is evasion from programmed cell suicide (apoptosis), most notably mitochondrial apoptosis that is controlled by the BCL-2 proteins which govern life and death decisions. Despite our wealth of knowledge on apoptosis, we lack an understanding how cells on the path to become cancer cells escape elimination. Therefore, one major question of BEAT IT is whether and how different DNA abnormalities rewire the BCL-2 network to nudge blood cells towards becoming cancerous. Comprised of four research groups, BEAT IT will leverage expertise in preclinical blood cancer models, cell death, mitochondrial biology, advanced imaging and large data processing. Using our new understanding of how cells with DNA aberrations become cancerous, we will identify new therapeutic targets and opportunities which can exploited to prevent cancer progression, or even onset.