Abstract
The unfolded protein response (UPR), an endoplasmic reticulum (ER) stress-induced signaling cascade, is mediated by three major stress sensors IRE-1α, PERK, and ATF6α. Studies described the UPR as a critical network in selection, adaptation, and survival of cancer cells. While previous reviews focused mainly on solid cancer cells, in this review, we summarize the recent findings focusing on acute leukemias. We take into account the impact of the underlying genetic alterations of acute leukemia cells, the leukemia stem cell pool, and provide an outline on the current genetic, clinical, and therapeutic findings. Furthermore, we shed light on the important oncogene-specific regulation of individual UPR signaling branches and the therapeutic relevance of this information to answer the question if the UPR could be an attractive novel target in acute leukemias.
Highlights
The therapy of acute leukemias either originating from myeloid (acute myeloid leukemia (AML)) or lymphoid lineage (acute lymphoblastic leukemia (ALL)) has improved in recent decades, the heterogeneous genetic landscape of these diseases causes relapse in the majority of patients
To maintain cellular protein homeostasis and to be shielded against stress stimuli accumulating within the endoplasmic reticulum (ER) causing “ER stress,” cells are mainly dependent on the cytoprotective network of the unfolded protein response (UPR)
Initial studies showed that both X-box binding protein 1 (XBP1) and GRP78 were higher expressed in Philadelphia chromosome (Ph)+ leukemia cell lines, while detailed functional studies were missing [84]
Summary
The therapy of acute leukemias either originating from myeloid (acute myeloid leukemia (AML)) or lymphoid lineage (acute lymphoblastic leukemia (ALL)) has improved in recent decades, the heterogeneous genetic landscape of these diseases causes relapse in the majority of patients. UPR and C/EBPα in AML Studies showed that the IRE-1α/XBP1s branch of the UPR was activated in 17.4 % of AML cases [51, 52]. UPR and hypoxia in AML Hypoxic environments such as the bone marrow, where the majority of leukemia cells reside [62], lead to activation of the hypoxia-inducible factor (HIF) pathway.
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