SpringerLink
Log in

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

  • Basic Science Article
  • Published:
Pediatric Research Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1: Correlation of EMP1 expression with cytogenetic abnormalities and with outcome in patients from the TARGET database.
Fig. 2: Independent prognostic analysis of EMP1.
Fig. 3: EMP1 surface expression in pediatric acute myeloid leukemia patient and umbilical cord blood samples.
Fig. 4: EMP1 surface expression in white blood cell types.
Fig. 5: Immunohistochemical analysis of EMP1 expression in healthy tissue samples (n = 12).
Fig. 6: EMP1 expression in hematological cell lines.

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article [and its supplementary information files].

References

  1. Zwaan, C. M. et al. Collaborative efforts driving progress in pediatric acute myeloid leukemia. J. Clin. Oncol. 33, 2949–2962 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Rasche, M. et al. Successes and challenges in the treatment of pediatric acute myeloid leukemia: a retrospective analysis of the AML-BFM trials from 1987 to 2012. Leukemia 32, 2167–2177 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  3. Maloney, K. W. et al. Outcome in children with standard-risk B-cell acute lymphoblastic leukemia: results of children’s oncology group trial AALL0331. J. Clin. Oncol. 38, 602–612 (2020).

    Article  CAS  PubMed  Google Scholar 

  4. Stelmach, P. & Trumpp, A. Leukemic stem cells and therapy resistance in acute myeloid leukemia. Haematologica 108, 353–366 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Depreter, B. et al. Deciphering molecular heterogeneity in pediatric AML using a cancer vs. normal transcriptomic approach. Pediatr. Res. 89, 1695–1705 (2021).

    Article  CAS  PubMed  Google Scholar 

  6. Creutzig, U. et al. Diagnosis and management of acute myeloid leukemia in children and adolescents: recommendations from an international expert panel. Blood 120, 3187–3205 (2012).

    Article  CAS  PubMed  Google Scholar 

  7. Barlogis, V. et al. Late cardiomyopathy in childhood acute myeloid leukemia survivors: a study from the L.E.A. program. Haematologica 100, e186–e189 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Taylor, V., Welcher, A. A., Program, A. E. & Suter, U. Epithelial membrane protein-1, peripheral myelin protein 22, and lens membrane protein 20 define a novel gene family. J. Biol. Chem. 270, 28824–28833 (1995).

    Article  CAS  PubMed  Google Scholar 

  9. Ng, S. W. K. et al. A 17-gene stemness score for rapid determination of risk in acute leukaemia. Nature 540, 433–437 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Lin, S.-Y. et al. A 6-membrane protein gene score for prognostic prediction of cytogenetically normal acute myeloid leukemia in multiple cohorts. J. Cancer 11, 251–259 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Lange, B. J. et al. Outcomes in CCG-2961, a children’s oncology group phase 3 Trial for untreated pediatric acute myeloid leukemia: a report from the Children’s Oncology Group. Blood 111, 1044–1053 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gamis, A. S. et al. Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children’s oncology group trial AAML0531. J. Clin. Oncol. 32, 3021–3032 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Pollard, J. A. et al. Sorafenib in combination with standard chemotherapy for children with high allelic ratio FLT3/ITD+ acute myeloid leukemia: a report from the children’s oncology group protocol AAML1031. J. Clin. Oncol. 40, 2023–2035 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Aplenc, R. et al. Bortezomib with standard chemotherapy for children with acute myeloid leukemia does not improve treatment outcomes: a report from the Children’s Oncology Group. Haematologica 105, 1879–1886 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Balgobind, B. V. et al. Evaluation of gene expression signatures predictive of cytogenetic and molecular subtypes of pediatric acute myeloid leukemia. Haematologica 96, 221–230 (2011).

    Article  CAS  PubMed  Google Scholar 

  16. Zhang, N. et al. Unraveling the structures, functions and mechanisms of epithelial membrane protein family in human cancers. Exp. Hematol. Oncol. 11, 69 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ariës, I. M. et al. EMP1, a novel poor prognostic factor in pediatric leukemia regulates prednisolone resistance, cell proliferation, migration and adhesion. Leukemia 28, 1828–1837 (2014).

    Article  PubMed  Google Scholar 

  18. Wang, J. et al. EMP1 regulates cell proliferation, migration, and stemness in gliomas through PI3K-AKT signaling and CD4. J. Cell. Biochem. 120, 17142–17150 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Hsu, C.-H. et al. Transcriptome profiling of pediatric core binding factor AML. PloS One 10, e0138782 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ichikawa, H. et al. Common gene expression signatures in t(8;21)-and inv(16)-acute myeloid leukaemia. Br. J. Haematol. 135, 336–347 (2006).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Our gratitude goes to all patients and their parents for their participation in the study, as well as to the data managers involved in the clinical trials. The authors thank the Cord Blood Bank, the staff of all the involved Pediatric Hematology and Oncology sites, and the Pathology Department of Ghent University Hospital (Ghent, Belgium) for providing samples. A special thanks to Irem Kaya for the sample preparation of the immunohistochemistry analysis. The results published here are in whole or partly based upon data generated by the Therapeutically Applicable Research to Generate Effective Treatments (https://www.cancer.gov/ccg/research/genomesequencing/target) initiative, phs000218. The data used for this analysis are available at the Genomic Data Commons (https://portal.gdc.cancer.gov).

Funding

This research was funded by Kom op tegen Kanker (grants to B.D.M. and T.L.), vzw Kinderkankerfonds (grant to B.D.M.), and the Olivia Hendrickx Research Fund (grant to L.V.C.).

Author information

Author notes

  1. These authors contributed equally: Tim Lammens, Barbara De Moerloose.

Authors and Affiliations

  1. Ghent University, Department of Internal Medicine and Pediatrics, Ghent, Belgium

    Laurens Van Camp, Tim Lammens & Barbara De Moerloose

  2. Ghent University Hospital, Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent, Belgium

    Laurens Van Camp, Eva Terras, Tim Lammens & Barbara De Moerloose

  3. AZ Delta General Hospital, Department of Laboratory Medicine, Roeselare, Belgium

    Barbara Depreter

  4. Vrije Universiteit Brussel (VUB), Department Pharmaceutical Sciences (FARM), Brussels, Belgium

    Barbara Depreter

  5. Ghent University Hospital, Department of Pathology, Ghent, Belgium

    Jilke De Wilde & Malaïka Van der Linden

  6. Ghent University, Department of Biomolecular Medicine, Ghent, Belgium

    Jilke De Wilde & Malaïka Van der Linden

  7. Ghent University Hospital, Laboratory of Hematology, Ghent, Belgium

    Mattias Hofmans

  8. Ghent University, Department of Diagnostic Sciences, Ghent, Belgium

    Mattias Hofmans

  9. Centre Hospitalier Chrétien (CHC), MontLégia, Division of Pediatric Hematology-Oncology, Liège, Belgium

    Christophe Chantrain

  10. Queen Fabiola Children’s University Hospital, Department of Pediatric Hematology-Oncology, Brussels, Belgium

    Laurence Dedeken

  11. University Hospital Saint-Luc, Department of Pediatric Hematology Oncology, Brussels, Belgium

    An Van Damme

  12. University Hospital Gasthuisberg, Department of Pediatrics, Leuven, Belgium

    Anne Uyttebroeck

Authors
  1. Laurens Van Camp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Barbara Depreter
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jilke De Wilde
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mattias Hofmans
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Malaïka Van der Linden
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Eva Terras
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Christophe Chantrain
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Laurence Dedeken
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. An Van Damme
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Anne Uyttebroeck
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tim Lammens
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Barbara De Moerloose
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization, L.V.C., B.D., T.L. and B.D.M.; methodology, L.V.C., J.D.W., M.H., M.V.D.L., E.T., and T.L.; formal analysis, L.V.C.; resources, A.U., A.V.D., L.D., C.C., T.L. and B.D.M.; writing—original draft preparation, L.V.C.; writing—review and editing, all authors; supervision, T.L and B.D.M.; funding acquisition, L.V.C., B.D.M. and T.L. All authors have read and agreed to the published version of the manuscript.

Corresponding author

Correspondence to Tim Lammens.

Ethics declarations

Competing interests

All authors declare to have no potential conflicts of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Consent Statement

The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of the Ethics Committee of the University Hospital of Ghent (EC2015-1443 1 April 2016 and EC2019-0294 20 March 2020). Informed consent was obtained from all subjects involved in the study.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Van Camp, L., Depreter, B., De Wilde, J. et al. Acute myeloid leukemia stem cell signature gene EMP1 is not an eligible therapeutic target. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03341-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41390-024-03341-x

  • Springer Nature America, Inc.

Search

Navigation