Neural Progenitor Cells Deficient In Bax And Bak Manifest Progressive Hyperplasia And Tumorigenesis

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The pro-apoptotic BCL-2 family proteins BAX and BAK serve as essential gatekeepers of the intrinsic apoptotic pathway and, when activated, transform into pore-forming homo-oligomers that permeabilize the mitochondrial outer membrane. Deletion of Bax and Bak causes marked resistance to many death stimuli in a variety of cell types. Bax−/−Bak−/− mice are predominantly non-viable and survivors exhibit multiple developmental abnormalities characterized by cellular excess, including accumulation of neural progenitor cells in the periventricular, hippocampal, cerebellar, and olfactory bulb regions of the brain. To explore the long-term pathophysiologic consequences of BAX/BAK deficiency in the central nervous system, we generated Bak−/− mice with conditional deletion of Bax in Nestin-positive cells. Aged mice manifest progressive brain enlargement with a profound accumulation of NeuN- and Sox2-positive neural progenitor cells within the subventricular zone niche. One-third of the mice develop frank masses comprised of the progenitor neurons, and in 20% of these cases, more aggressive, hypercellular tumors emerged. Interestingly, 60% of NestinCreBaxfl/flBak−/− mice harbor high-grade tumors within the testis interstitium, a peripheral site of Nestin expression. This mouse model of apoptotic blockade highlights the constitutive role of BAX/BAK in long-term regulation of Nestin-positive progenitor cell pools, with loss of function predisposing to adult-onset tumorigenesis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2367. doi:1538-7445.AM2012-2367