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Assessment of Ecotropic Viral Integration Site 2B (EVI2B) Gene in Juvenile Myelomonocytic Leukemia and Neurofibromatosis Type 1 NF1 Tumors

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Abstract

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease that affects the development and growth of various tissues. NF1 is a major risk factor for the development of malignancies, particularly malignant peripheral nerve sheath tumors, optic gliomas, and leukemia. NF1 encodes a neurofibromin. Three genes, EVI2A, EVI2B, and OMGP, are embedded within intron 27b of NF1. However, the function of these genes remains unclear. EVI2A and EVI2B encode for putative transmembrane proteins. Mouse homologs are associated with viral insertions involved in leukemia in mice. Mouse Evi2b has been identified as a direct target gene of C/EBPα, a transcription factor critical for myeloid differentiation. Also possible is that these genes are related to the leukemia observed in patients with NF1. These genes might act as modifiers of NF1 phenotypic variations. Therefore, we investigated the EVI2B gene in leukemia and NF1 tumors. We analyzed DNA from 10, 20, and 3 patients with NF1, leukemia, and NF1-leukemia, respectively, and six NF1 tumor tissues. DNA sequencing analysis was used to identify the viral integration sequence, and the protein amounts and EVI2B gene expression were analyzed by flow cytometry and quantitative real-time PCR techniques. The EVI2B gene expression was increased in cutaneous neurofibroma compared with the control both at the level of protein and mRNA. However, its expression in plexiform neurofibroma was decreased significantly at protein level and increased at mRNA level compare to control. Moreover, integration of 455 bases near the 3′ end of the exon was detected. When this integrated sequence was blasted into the NCBI retroviral genome database, an 87% match with the HIV-1 virus envelope gene was obtained. These preliminary results show that EVI2B might be important in NF1 tumorigenesis and leukemia.

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Correspondence and requests for materials should be addressed to Sukriye AYTER and Parisa SHARAFI.

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Acknowledgements

We also thank Prof. Dr. Rıza Köksal ÖZGÜL, and the staff of the Hacettepe University, Faculty of Medicine, Institute of Child Health, Department of Metabolism, Ankara, Turkey, for their permission to use the DNA sequencing facility.

Funding

This study was supported by TÜBİTAK (Project Numbers: 107S96). We also thank Prof. Dr. Rıza Köksal ÖZGÜL, and the staff of the Hacettepe University, Faculty of Medicine, Institute of Child Health, Department of Metabolism, Ankara, Turkey, for their permission to use the DNA sequencing facility.

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Authors and Affiliations

  1. Department of Medical Biology and Genetics, Faculty of Medicine, TOBB University of Economics and Technology, Ankara, Turkey

    Parisa Saharafi & Sukriye Ayter

  2. Center for Stem Cell Research and Development (PEDI-STEM), Hacettepe University, Ankara, Turkey

    İrem Akar

  3. Department of Dermatology, School of Medicine, Hacettepe University, Ankara, Turkey

    Sibel Ersoy-Evans

  4. Department of Pediatrics, Pediatric Neurology, School of Medicine, Hacettepe University, Ankara, Turkey

    Banu Anlar

  5. Department of Pediatrics, Pediatric Oncology, School of Medicine, Hacettepe University, Ankara, Turkey

    Ali Varan

  6. Department of Plastic Reconstructive and Aesthetic Surgery, School of Medicine, Hacettepe University, Ankara, Turkey

    Ibrahim Vargel

  7. School of Medicine, Department of Hematology, Hacettepe University, Ankara, Turkey

    Mualla Cetin

Authors
  1. Parisa Saharafi
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  2. İrem Akar
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  7. Mualla Cetin
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  8. Sukriye Ayter
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Contributions

The main idea of this project and Conceptualization developed by SA. The experiments were designed by SA and PS. SE-E, BA and AV visited, diagnosed and acquired the patients with NF1. MC visited, diagnosed and acquired the patients with Leukemia. IV performed the surgery on NF1 patients and acquired cutaneous and plexiform neurofibromas. The experiments performed by PS. The flow cytometry part of experiment performed by İA and PS. SA and PS wrote the main manuscript text. IA wrote the flow cytometry methodology, result and prepared the figure related to it. The rest of tables and figures were prepared by PS. All authors reviewed the manuscript.

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Correspondence to Sukriye Ayter.

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The authors declare no competing interests.

Ethical Approval and Consent to Participate

The study protocol was approved by the Institutional Ethics Committee of Hacettepe University, ANKARA (Report number: GO16/674–07, Date:08.11.2016). Written informed consent was obtained from all participants.

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Saharafi, P., Akar, İ., Ersoy-Evans, S. et al. Assessment of Ecotropic Viral Integration Site 2B (EVI2B) Gene in Juvenile Myelomonocytic Leukemia and Neurofibromatosis Type 1 NF1 Tumors. Biochem Genet 62, 1263–1276 (2024). https://doi.org/10.1007/s10528-023-10480-z

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  • DOI: https://doi.org/10.1007/s10528-023-10480-z

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