Abstract 4728: Apoptotic priming is regulated by a developmental program and predisposes children to therapy-induced toxicity

Abstract

Abstract Pediatric cancer patients frequently suffer higher levels of treatment-induced toxicities than adults, limiting the use of potentially curative therapies. For example, brain irradiation contributes to the cure of medulloblastomas in 80% of children yet also causes cell death in healthy neurons, resulting in a permanent and devastating loss of IQ. Likewise, children commonly experience dose-limiting cardiotoxicity from doxorubicin treatment. These treatments are comparatively well tolerated in adults yet the basis for this dramatic contrast in sensitivity is unknown. Both radiation and cytotoxic chemotherapies can induce an apoptotic cell death, prompting us to hypothesize that apoptosis may be regulated in a fundamentally different manner in children versus adults. By testing the functional state of the apoptotic pathway in tissues with BH3 Profiling, we found that healthy brain, heart and kidney tissues from young mice are extremely sensitive to pro-apoptotic signals and are therefore “primed for apoptosis.” In stark contrast, these same tissues are completely insensitive to even saturating amounts of pro-apoptotic signals in adult mice. Apoptosis could be triggered in adult brain, heart or kidney cells only when complemented with exogenous BAX protein suggesting that these tissues lack sufficient levels of BAX or BAK for mitochondrial permeabilization and are thus “incompetent for apoptosis.” Immunoblotting revealed that BAX and BAK protein levels are strongly downregulated in these tissues during postnatal development and become nearly undetectable by adulthood, along with several other components of the apoptotic machinery. Parallel studies with spleen and bone marrow demonstrated high levels of apoptotic priming in young animals which continued into adulthood, highlighting the organ-specific nature of apoptosis regulation. In agreement with these findings, we observed apoptotic cell death in response to radiation damage in the brain, heart and kidneys of early postnatal but not adult mice. Likewise, the extent of doxorubicin-induced damage to cardiac tissue correlated strongly with changes in apoptotic priming and competence. Furthermore, we utilized BAX and/or BAK knockout mice to characterize the pivotal roles of these proteins in regulating apoptotic competence and damage responses in somatic tissues. We extended these findings to humans by BH3 profiling normal brain tissue and confirmed that brain tissue in young children is primed to undergo apoptosis while in adults it is apoptotically incompetent. Finally, we identified the epigenetic mechanisms that modulate apoptotic pathways during postnatal development. Our findings elucidate the molecular mechanisms responsible for the devastating vital organ sensitivity to damage in children and a strategy for its prevention. Citation Format: Kristopher A. Sarosiek, Michael Ziller, Cameron Fraser, Patrick Bhola, Jeremy Ryan, Jing Deng, Brian Jian, Marti Goldenberg, Joseph Madsen, Ruben Carrasco, Shenandoah Robinson, Javid Moslehi, Anthony Letai. Apoptotic priming is regulated by a developmental program and predisposes children to therapy-induced toxicity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4728. doi:10.1158/1538-7445.AM2015-4728