In the ER the transmembrane proteins PERK, IRE1a and ATF6 act as sentinels, which sense increasing stress and signal into the cytoplasm and nucleus. Upon activation, IRE1 e.g. unleashes an intrinsic endoribonuclease activity, which leads to alternative splicing of precursor XBP1 mRNA to yield the mature XBP1 transcription factor that is required for the synthesis of ERresident chaperones and other genes important for ER function. ATF6 is eventually translocated to the Golgi, where it is proteolytically processed to become an activated transcription factor that is involved in the upregulation of XBP1 mRNA and other UPR genes. PERK and related kinases in contrast phosphorylate the translation initiation factor eIF2a at a critical serine residue leading to inactivation of eIF2a and the subsequent global inhibition of protein synthesis. In parallel, expression of the transcription factor ATF4 is selectively enhanced along with the expression of downstream target genes such as GADD34, CHOP/GADD153 and others, which participate in the control of cellular redox status and cell death. The block in general protein synthesis imposed by eIF2a Evofosfamide phosphorylation is reversed by the activity of the type I Ser/Thr specific protein phosphatase PP1a/GADD34 complex. This complex apparently dephosphorylates eIF2a again when ERhomeostasis is restored and allows the cell to PD325901 resume protein synthesis. Salubrinal, a low molecular weight compound, has been demonstrated to inhibit the PP1a/GADD34 complex and to protect neuronal cells against ER stress, probably by extending the period, in which the prolonged reduction of denovo protein synthesis can help the cell to regain protein folding capacity, to degrade the surplus of unfolded proteins and to recover from ER stress. Here I report that salubrinal did not protect Bcr-Abl –positive or negative leukemic cells from proteasome inhibitor-mediated ER stress and toxicity but in contrast synergistically enhanced apoptotic cell death by further boosting ER-stress, a finding, which may have impact on the future design of treatment modalities for hematological cancers. Thapsigargin, an inhibitor of the ER calcium pump, is a genuine ER stresser, capable of activating all three UPR pathways and of inducing cell death. In contrast, although proteasome inhibitor treatment has been associated with ER stress and the UPR, the specific contribution of proteasome inhibitors to ER stress-mediated cell death may be obscured by the multifaceted additional impact of these inhibitors on other regulatory pathways. It was of interest therefore to determine, whether salubrinal would also prevent classical, thapsigargin-mediated ER stress mediated cell death in K562 cells or whether the response to salubrinal would instead reflect cell type specific differences. As demonstrated in Fig. 8, coadministration of salubrinal and of thapsigargin at low, only mildly toxic concentrations did not protect K562 cells from thapsigargin-mediated stress and toxicity and instead led to a marked increase in apoptosis. This observation suggested that the salubrinal–mediated effects were independent from the nature of the ER stressor and rather appeared to be due to intrinsic cell type specific differences in the ER stress signaling mechanisms between the leukemic cells examined here and e.g. neural PC-12 cells.