Analysis of unfolded protein response in hematological malignancy

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The unfolded protein response (UPR) is activated in various tumors and may play a crucial role in tumor growth. However, the role of the UPR in leukemia remains unclear. Therefore, to define the role of the UPR in leukemogenesis, we investigated UPR activation in a cell line expressing the representative oncogene Bcr-Abl (B-A). The expression of UPR-related proteins, namely, X-box-binding protein (XBP1) and glucose-regulated protein 78 (GRP78), and of phosphorylated eukaryotic translation initiation factor 2α (eIF2α) was increased in B-A. Using a luciferase assay, we observed that Bcr-Abl induced high levels of the transcriptional activity of the cis-acting UPR element. Moreover, the mRNA levels of the UPR-related genes, namely, spliced form of XBPI; GRP78; and p58IPK, a cellular inhibitor of the RNA-dependent protein kinase, increased in B-A. UPR inhibition using inositol-requiring enzyme lα (IRE1α) or activating transcription factor 6 (ATF6) dominant-negative mutants diminished the ability of Bcr-Abl to protect the cells from etoposide- and imatinib-induced apoptosis; however, it had no effect on the proliferation of Bcr-Abl-transformed cells. We also noted that the expression of UPR-related genes in primary leukemia cells from Philadelphia chromosome (Ph) -positive cells was higher than that in the control by quantitative reverse transcription-polymerase chain reaction assay. Thus, our results suggested that UPR is a downstream target of Bcr-Abl and plays an anti-apoptotic role of Bcr-Abl in Ph-positive leukemia cells.