Survival and chemoresistance of chronic lymphocytic leukemia (CLL) cells can be attributed to aberrant apoptosis signaling. CLL cells intrinsically express high levels of the anti-apoptotic protein Bcl-2 and are able to upregulate other pro-survival proteins like Mcl-1, Bcl-xL and A1 in response to different microenvironmental stimuli. Paradoxically, pro-apoptotic proteins Bmf, Bim and Noxa are expressed at high levels as well and can be interpreted as failed attempts of the normal checkpoint machinery to eliminate these aberrant cells. Additionally, Puma becomes upregulated in response to treatment with the cytotoxic agent Fludarabine. However, under ex vivo conditions CLL cells readily undergo apoptosis. This demonstrates the existence of a primed and functional cell death machinery, which becomes overruled by survival signals from the microenvironment in vivo. Therefore, this study aims to identify the relevant apoptosis mediators and upstream signals that could be utilized to tip the balance towards cell death induction in CLL cells. Relevant survival signals from the microenvironment likely include antigenic stimulation, crosstalk between CLL cells and stromal cells and T cell – CLL cell interactions. We therefore aim to (i) identify the Bcl-2 family members whose loss or overexpression significantly impacts tumor development, (ii) define the microenvironmental inputs and upstream pathways that result in the modulation of these critical apoptosis regulators and (iii) model data-based therapeutic combinations that simultaneously target relevant signaling pathways and enhance the cell death signal via the use of appropriate BH3 mimetics. In order to sufficiently recreate the required multifaceted microenvironmental cues, complex in vitro co-culture systems using primary human and murine samples will be employed as well as animal models with genetic manipulations of Bcl-2 family members. This will allow us to elucidate the intricate dependency of CLL on its microenvironment and to obtain valuable information on human CLL behavior.
Alexander Egle (Priv.-Doz. OA)
Daniela Asslaber (Postdoc)
Nicole Maeding (PhD Student)
Cooperation within FOR2036
Andreas Villunger, Miriam Erlacher, Philipp Jost