Abstract
Accumulation of unfolded or misfolded proteins within the endoplasmic reticulum triggers the unfolded protein response (UPR). Evidence from several studies suggests that the UPR is activated in various tumors and might play a crucial role in tumor growth. For example, in vitro activation of the UPR alters the sensitivity of tumor cells to chemotherapeutic agents. The role of the UPR in hematological malignancies remains unclear, however. We therefore used real-time RT-PCR to quantitatively assess expression of UPR-related genes in clinical samples [peripheral blood (PB), bone marrow (BM) and lymph node (LN)] from 9 newly diagnosed patients with acute myeloid leukemia (AML), 5 with acute lymphoid leukemia (ALL), 4 with multiple myeloma (MM), 12 with Non-Hodgkin’s lymphoma, 1 with Hodgkin’s lymphoma and 6 with infectious lymphadenopathy. Thirteen healthy controls were also examined. Evaluated was the mRNA expression of a spliced form of X-box DNA-binding protein (XBP1), ER degradation enhancing a-mannosidase-like protein (EDEM), C/EBP-homologous protein (CHOP) and glucose regulated protein 78 (GRP78). We found the transcription levels of all four of these genes to be significantly higher in leukemic blast cells and myeloma cells than in control BM cells or PB mononuclear cells. In particular, leukemic cells from Philadelphia chromosome-positive ALL and aggressive MM cells showed higher levels of UPR-related gene expression. Thus, activation of the UPR might be associated with the malignant characteristics of leukemia and myeloma. By contrast, expression of UPR-related genes was not increased in lymphoma cells compared to LN cells from the patients with infectious lymphadenopathy.
The present study provides the first evidence that UPR-related genes are activated in acute leukemia and multiple myeloma cells. Thus, activation of the UPR might play an important role in the development and progression of some hematological malignancies. More comprehensive in vitro studies will be necessary to determine the magnitude of the role played by the UPR, to identify the most important components of the pathway, and to determine which stages of tumor development are regulated by the UPR.
Spliced XBP1 Levels Determine Sensitivity of Multiple Myeloma Cells to Proteasome Inhibitor Bortezomib Independent of the Unfolded Protein Response Mediator GRP78