Bcl-2 family members in the pathobiology and therapy of Chronic Lymphocytic Leukemia

In chronic lymphocytic leukaemia (CLL), the survival and chemoresistance of tumor cells, can be attributed to aberrant apoptosis signalling. Ex vivo, CLL cells readily undergo apoptosis, demonstrating that a primed and functional cell death machinery exists that is strongly overruled by microenvironmental survival cues in vivo. CLL cells intrinsically express high levels of the pro-survival protein Bcl-2 and can further upregulate Mcl-1, Bcl-XL, and A1 in response to a diverse number of microenvironmental signals. Paradoxically, high levels of the pro- apoptotic proteins Bim, Bmf, and Noxa are also expressed and can be interpreted as failed attempts of the normal checkpoint machinery to eliminate these aberrant cells. Puma is additionally upregulated upon treatment with the cytotoxic agent Fludarabine that is the mainstay of therapy. The proposed study aims to identify the relevant apoptosis mediators and upstream signals that could be engaged in order to tip the balance towards cell death in CLL, in the hope of developing novel treatment paradigms for this incurable disease. Relevant input survival signals from the microenvironment likely include antigenic stimulation, cellular adhesion, and T cell CLL interactions, thus offering the opportunity to study the impact of these diverse signalling pathways on the Bcl-2 rheostat in a malignant setting. We will therefore (i) identify the Bcl-2 family members whose loss or overexpression significantly impacts tumor development, (ii) stringently define the upstream microenvironmental signals and pathways that result in the modulation these critical apoptosis regulators, and (iii) develop smart therapeutic combinations that simultaneously target relevant signalling pathways and enhance the cell death signal via the use of the appropriate BH3 mimetic. As CLL displays such a intricate dependence on its microenvironment, both complex in vitro co-culture systems and animal models will be employed in our investigations in order to sufficiently recreate the multifaceted microenvironmental cues required, while also retaining some information on human CLL behavior.

No additional funding sources recorded.