BCL2 and B-cell chronic lymphocytic leukemia: However, when the adaptive responses of the UPR is overwhelmed by severe and persistent ER stress and ER homeostasis is not restored, the responses of the UPR change over from adaptive pro-survival to toxic pro-death and/or premature senescence as two tier safety mechanisms via the release of Ca2+, the upregulation of pro-apoptotic B cell chronic lymphocytic leukemia (CLL)/lymphoma 2 (BCL-2) family members, the production of reactive oxygen species (ROS), or the regulation of microRNAs [11,52].