The PKR-Like Endoplasmic Reticulum Kinase Promotes the Dissemination of Myc-Induced Leukemic Cells

Abstract

Hyperactive oncogenic Myc stimulates protein synthesis that induces the unfolded protein response, which requires the function of the eukaryotic translation initiation factor 2-alpha kinase 3, also known as protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK). Activated PERK acts to limit mRNA translation, enable proper protein folding, and restore the homeostasis in the endoplasmic reticulum. Given that Myc activation contributes to many types of lymphoid and myeloid human leukemias, we used a mouse model to examine the importance of PERK in development and progression of Mycinduced leukemias. We found that genetic ablation of Perk does not suppress the generation of the leukemic cells in the bone marrow. However, the cell-autonomous Perk deficiency restricts the dissemination of leukemic cells into peripheral blood, lymph nodes, and vital peripheral organs. Whereas the loss of the IFNAR1 chain of type I IFN receptor stimulated leukemia, Perk ablation did not stabilize IFNAR1, suggesting that PERK stimulates the leukemic cells' dissemination in an IFNAR1-independent manner. We discuss the rationale for using PERK inhibitors against Myc-driven leukemias. Implications: The role of PERK in dissemination of Myc-induced leukemic cells demonstrated in this study argues for the use of PERK inhibitors against leukemia progression.

Overexpression of HOXA10 is associated with unfavorable prognosis of acute myeloid leukemia

“…Cheng X et al reported that high expression of EIF2AK2 was associated with worse prognosis in AML, and it reduced DNA damage response by inhibiting ataxia-telangiectasia mutated (ATM) activation, leading to accretion of leukemia in mice model [67]. EIF2AK3 (also named as PKR-like endoplasmic reticulum kinase, PERK) is reported to promoted leukemia progress by stimulating the dissemination of leukemia cells in vivo [68]. So, the increased EIF2AK2/3 expression and activated ribosome pathway contributed to the worse outcomes in HOXA10-high patients.…”

Overexpression of HOXA10 is associated with unfavorable prognosis of acute myeloid leukemia

“…Cheng X et al reported that high expression of EIF2AK2 was associated with worse prognosis in AML, and it reduced DNA damage response by inhibiting ataxiatelangiectasia mutated (ATM) activation, leading to accretion of leukemia in mice model (69). EIF2AK3 (also named as PKR-like endoplasmic reticulum kinase, PERK) is reported to promoted leukemia progress by stimulating the dissemination of leukemia cells in vivo (70). So, the increased EIF2AK2/3 expression and activated ribosome pathway contributed to the worse outcomes in HOXA10-high patients.…”

Unfolded Protein Response in Leukemia: From Basic Understanding to Therapeutic Opportunities

“…These findings point to Myc/UFD1 signaling as a key driver of the ER stress response in T-ALL and suggest that this pathway could be exploited therapeutically [44]. Accordingly, PERK activity was recently shown to promote dissemination of leukemic cells into peripheral blood and lymph nodes and thus may play an important role in progression of Myc-driven leukemias [45].…”