The PERK signaling pathway as a marker of the unfolded protein response in patients with acute myeloid leukemia

TL;DR

The study found that the PERK pathway is active in acute myeloid leukemia patients, suggesting it could be a potential treatment target.

Contribution

This study is the first to evaluate PERK signaling as a marker of the unfolded protein response in newly diagnosed AML patients.

Findings

AML patients had significantly higher levels of PERK-related biomarkers compared to healthy controls.

eIF2AK3 levels decreased significantly after remission-induction therapy in AML patients.

Strong correlations were observed between GRP78 and CHOP levels in AML patients.

Abstract

The protein kinase RNA-like endoplasmic reticulum kinase (PERK) pathway plays a critical role in preventing the accumulation of misfolded or unfolded proteins within the endoplasmic reticulum. In this study, the role of the PERK signaling pathway was evaluated in newly diagnosed, treatment-naïve patients with acute myeloid leukemia (AML).

Plasma levels of eukaryotic translation initiation factor 2-alpha kinase 3 (eIF2AK3), glucose-regulated protein 78 (GRP78), activating transcription factor 6 (ATF6), CCAAT/enhancer-binding protein homologous protein (CHOP), hypoxia-inducible factor-1 alpha (HIF-1α), and caspase 3 were measured by enzyme-linked immunosorbent assay in peripheral blood samples obtained from AML patients and healthy controls.

A total of 40 individuals were included, comprising 19 (47%) AML patients and 21 (53%) healthy controls. HIF-1α, eIF2AK3, GRP78, ATF6, CHOP, and caspase 3 levels were significantly higher in the AML group than in the control group (p = 0.019, 0.005, <0.001, 0.006, <0.001, and <0.001, respectively). No significant differences were observed in HIF-1α, GRP78, ATF6, CHOP, and caspase 3 levels between diagnosis and the 30th day of remission-induction therapy in the AML group, whereas a significant decrease was observed in eIF2AK3 levels (p = 0.049). At diagnosis, a strong positive correlation was found between GRP78 and CHOP levels (r = 0.740, p < 0.001), and a moderate positive correlation was detected between CHOP and caspase 3 levels (r = 0.514, p = 0.024) in the AML group. In the Cox regression analysis of the AML cohort, no statistically significant association was identified between overall survival and age, risk category, or biomarker levels (HIF-1α, eIF2AK3, GRP78, ATF6, CHOP, and caspase 3).

PERK and ATF6 signaling pathways were activated in patients with AML. Targeting the unfolded protein response pathway may represent a promising therapeutic strategy for patients with AML.