# GPR44-Dependent Regulation of the Selenoproteome by eIF4a3 in Murine Acute Myeloid Leukemia-Initiating Stem Cells

## TL;DR

This study explores how GPR44 regulates selenium metabolism in leukemia stem cells, impacting disease progression and survival.

## Contribution

The study reveals a novel link between GPR44 signaling, selenoprotein regulation, and leukemia progression.

## Key findings

- GPR44 deletion alters the selenoproteome, affecting redox homeostasis and leukemic cell survival.
- eIF4a3 upregulation in Gpr44−/− LICs suggests a mechanism for selenoprotein repression via SBP2 inhibition.
- Upregulation of SBP2 and SPS2 indicates an adaptive response to maintain selenium incorporation.

## Abstract

Acute myeloid leukemia (AML) remains an aggressive hematologic malignancy, with leukemia-initiating stem cells (LICs) playing a critical role in disease progression and therapeutic resistance. In this study, we investigated the role of GPR44, a G-protein coupled receptor of arachidonic acid-derived prostaglandin D2 (PGD2) and its cyclopentenone prostaglandins (CyPGs) metabolites, Δ12-PGJ2 and 15d-PGJ2, in regulating selenium metabolism and selenoprotein expression in AML LICs. Transplantation of Gpr44−/− LICs into donor mice led to aggressive leukemogenesis. Transcriptomic and proteomic analyses revealed that GPR44 deletion significantly altered the selenoproteome, with downregulation of Txnrd1, Txnrd3, Selenop, and Gpx2, while upregulating Gpx3, Gpx4, Selenoo, and Msrb1. These findings suggest that GPR44 influences redox homeostasis and leukemic cell survival by modulating selenium utilization. Notably, increased expression of eIF4a3 in Gpr44−/− LICs suggested a potential mechanism for selective selenoprotein repression through SECIS-binding protein 2 (SBP2) inhibition. Additionally, upregulation of SBP2 and selenophosphate synthetase 2 (SPS2) indicated an adaptive response to maintain selenium incorporation. Given the role of selenium in redox balance, metabolism, and immune function, targeting selenium metabolism in GPR44-expressing AML may offer a novel therapeutic approach. Our findings reveal a previously unrecognized link between GPR44 signaling, selenium metabolism, and leukemia progression, warranting further studies to explore selenoprotein-targeting strategies for AML treatment.