Programmed cell death is crucial for the development of multiple cell lineages and organs, as well as the maintenance of normal tissue homeostasis. For example, whereas pathologic cellular survival is seen in cancer and autoimmune diseases, excessive cellular demise is found in diseases such as neurodegeneration and myocardial infarction. The goal of the laboratory is to rigorously define and elucidate the cellular signaling network that dictates life and death in appropriate cellular contexts. This knowledge is basic to developing selective therapeutics.
Therefore, a core focus of the laboratory is the expansive family of BCL-2 proteins. They comprise an intricate network of guardian and executioner proteins that govern the core pathway for programmed cell death in mammals. The role of the pro-apoptotic pore forming BCL-2 proteins in the development and maintenance of malignancy is a fundamental molecular process studied by the laboratory.
Severe Apoptotic Blockades in Neural Stem Cells
Within the adult brain apoptosis helps to regulate a pool of repopulating neural progenitor cells that reside in the perivascular niche of the subventricular zone (SVZ) and migrate along the rostral migratory stream to the olfactory bulb and to sites of injury. The long-term self-renewal capacity of such cell populations within the brain represents a potential vulnerability for oncogenesis should the critical balance between progenitor cell life, death and differentiation become deregulated. Understanding how aged neural stem cells are corrupted is important not only for treatment of brain cancer, but also for our ability to harness them for regenerative medicine.
One technique used by the laboratory for these studies uses conditional mouse knockouts. In this way we have shown that loss of BAX and BAK results in a massive proliferation of neural progenitor/stem cells that occasionally form large circumscribed masses. It is of great interest to determine whether BAX and BAK act solely in neural stem cells through their defined apoptotic functions, or if they have new unrevealed roles in cellular homeostasis. In either case, the commonalities shared by BAX BAK double knockout progenitors and cancer stem cells, including the capacity for self-renewal and profound apoptotic resistance, underscore the utility of this mouse model in delineating the importance of: (1) brain tumor initiating cells, (2) brain cancer stem cells and (3) additional genetic events that occur during aging that drive discrete subtypes of cancer. They are also informative regarding what therapeutic modalities will be required to overcome them. [Figure 1]
Apoptotic Resistance in Mantle Cell Lymphoma
Another apoptotic defect occurs in mantle cell lymphoma (MCL), a highly aggressive B-cell lymphoma resistant to conventional chemotherapy. Although defined by the characteristic t(11;14) translocation, MCL has not been recapitulated in transgenic mouse models of cyclin D1 overexpression alone. Frequent biallelic deletion of the pro-apoptotic BCL-2 family protein BIM suggests that it might act as a tumor suppressor. Chief among the killer BH3-only proteins, BIM exhibits the most broad-ranging BCL-2 protein interactions, engaging all of the anti-apoptotic proteins with high affinity and also directly triggering death effectors, such as BAX. [Figure 2]
We have developed a genetically-engineered mouse model of MCL where disease was triggered by immune stimulation in the context of both cyclin D1 overexpression and deletion of pro-apoptotic Bim in B-cells, recapitulating two common cytogenetic abnormalities seen in human MCL. This model may be especially useful for studying mantle cell biology, the progression to MCL, and the response to experimental therapeutics. [Figure 3]