Description:
<jats:title>Abstract</jats:title>
<jats:p>We previously showed that B cell receptor (BCR) induced apoptosis in lymphoma required suppression of PI-3K [Carey GB, Scott DW (2001) J. Immunol, 166: 1618-]. PI-3K stimulates mTOR, a suppressor of autophagy and mitophagy. In addition, Bcl-XL blocks BCR-driven apoptosis in lymphoma, although the underlying mechanism is unclear. In contrast, a recent study demonstrated that Bcl2 overexpression blocked BCR-driven apoptosis, but not the induction of autophagy [Watanabe et al BBRC (2008) 19;374(2):274-]. Therefore the present study examined autophagic and mitophagic responses following BCR crosslinking on parental WEHI-231 lymphoma cells or on a derivative expressing high levels of Bcl-XL (WEHI-231/Bcl-XL). The results confirmed dramatic mitochondrial dysfunction followed by apoptosis in WEHI-231 compared to WEHI-231/Bcl-XL. BCR-crosslinking resulted in rapid and massive induction of the autophagic response in parental WEHI-231 compared to WEHI-231/Bcl-XL. Furthermore, treatment with STF-62247, a small molecule inducer of autophagy, resulted in apoptosis in WEHI-231 but not WEHI-231/Bcl-XL cells. These data suggest that Bcl-XL prevents BCR-driven apoptosis in lymphoma via blocking autophagic and mitophagic responses. Hence, these studies demonstrate specific roles of BclXL and bcl2 in BCR-driven death responses. Lastly, combinations of small molecule autophagy inducers and Bcl-XL antagonists may prove to be effective in addressing lymphoma.</jats:p>