Acute myeloid leukemia stem cell signature gene EMP1 is not an eligible therapeutic target

Laurens Van Camp; Barbara Depreter; Jilke De Wilde; Mattias Hofmans; Malaïka Van der Linden; Eva Terras; Christophe Chantrain; Laurence Dedeken; An Van Damme; Anne Uyttebroeck; Tim Lammens; Barbara De Moerloose

doi:10.1038/s41390-024-03341-x

Acute myeloid leukemia stem cell signature gene EMP1 is not an eligible therapeutic target

Pediatr Res. 2024 Jun 15. doi: 10.1038/s41390-024-03341-x. Online ahead of print.

Authors

Laurens Van Camp^{1

2}, Barbara Depreter^{3

4}, Jilke De Wilde^{5

6}, Mattias Hofmans^{7

8}, Malaïka Van der Linden^{5

6}, Eva Terras², Christophe Chantrain⁹, Laurence Dedeken¹⁰, An Van Damme¹¹, Anne Uyttebroeck¹², Tim Lammens^#^{13

14}, Barbara De Moerloose^#^{1

2}

Affiliations

¹ Ghent University, Department of Internal Medicine and Pediatrics, Ghent, Belgium.
² Ghent University Hospital, Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent, Belgium.
³ AZ Delta General Hospital, Department of Laboratory Medicine, Roeselare, Belgium.
⁴ Vrije Universiteit Brussel (VUB), Department Pharmaceutical Sciences (FARM), Brussels, Belgium.
⁵ Ghent University Hospital, Department of Pathology, Ghent, Belgium.
⁶ Ghent University, Department of Biomolecular Medicine, Ghent, Belgium.
⁷ Ghent University Hospital, Laboratory of Hematology, Ghent, Belgium.
⁸ Ghent University, Department of Diagnostic Sciences, Ghent, Belgium.
⁹ Centre Hospitalier Chrétien (CHC), MontLégia, Division of Pediatric Hematology-Oncology, Liège, Belgium.
¹⁰ Queen Fabiola Children's University Hospital, Department of Pediatric Hematology-Oncology, Brussels, Belgium.
¹¹ University Hospital Saint-Luc, Department of Pediatric Hematology Oncology, Brussels, Belgium.
¹² University Hospital Gasthuisberg, Department of Pediatrics, Leuven, Belgium.
¹³ Ghent University, Department of Internal Medicine and Pediatrics, Ghent, Belgium. tim.lammens@ugent.be.
¹⁴ Ghent University Hospital, Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent, Belgium. tim.lammens@ugent.be.

^# Contributed equally.

PMID: 38879624
DOI: 10.1038/s41390-024-03341-x

Abstract

Background: Relapse in pediatric acute myeloid leukemia (pedAML) patients is known to be associated with residual leukemic stem cells (LSC). We have previously shown that epithelial membrane protein 1 (EMP1) is significantly overexpressed in LSC compared to hematological stem cell fractions. EMP1 was also documented as part of the 17-gene stemness score and a 6-membrane protein gene score, both correlating high EMP1 expression with worse overall survival. However, its potential as a therapeutic target in pedAML is still unexplored.

Methods: Association analyses of EMP1 expression with clinical and molecular AML characteristics were performed. Expression of EMP1 was evaluated in pedAML and cord blood samples. Expression in normal blood cells and tissues was evaluated by flow cytometry and immunohistochemistry, respectively.

Results: In silico analyses showed variable mRNA expression of EMP1 in multiple pedAML datasets, and a significant correlation between high EMP1 transcript levels and the presence of inv(16). Flow cytometry showed overexpression of EMP1 in pedAML samples, as well as expression in normal blood subsets. Importantly, immunohistochemistry revealed EMP1 expression in multiple normal tissues.

Conclusion: Although EMP1 presents as an interesting membrane-associated target in pedAML, its abundant expression in normal blood cells and tissues will impede it from further exploration as a therapeutic target.

Impact: EMP1 is highly expressed in multiple cancer types, but expression in acute myeloid leukemia (AML) and normal tissues is unexplored. As EMP1 is investigated in other cancer types, expression in normal tissues and blood cells is relevant in predicting the success of EMP1-targeted therapies. In this study, we showed expression of EMP1 in multiple tissues, predicting high on-target off-tumor toxicity, which will warn other researchers of possible toxicities when generating EMP1-targeted therapy. Finally, we showed that high EMP1 expression is associated with better overall survival of pediatric AML patients, reducing the need for EMP1-targeted therapy.