Perforin and granzyme B gene expression is associated with a short survival time in patients with multiple myeloma

Authors

DOI:

https://doi.org/10.33448/rsd-v11i14.36237

Keywords:

Perforin; Granzyme B; Multiple myeloma; Natural Killer cell; Cytotoxic T Lymphocytes.

Abstract

Objectives: Perforin and granzyme B are essential proteins for protective immune responses mediated by Cytotoxic T Lymphocytes (CTLs) and Natural Killer cells (NK) against cancers, especially those of hematological origin. Our study investigated polymorphisms in the perforin gene (PRF1) and quantified the levels of the perforin and granzyme B proteins in patients with multiple myeloma (MM). Methods: The PRF1 coding region was evaluated in 58 patients with MM and 78 healthy individuals using direct sequencing. Quantitative real-time PCR was performed to quantify gene expression, and flow cytometry was used to determine the intracellular protein levels. Results: We did not observe differences in the allele frequencies of polymorphisms in the PRF1 gene as well as in perforin and granzyme B protein expression between patients with MM and healthy individuals. However, reduced expression of perforin or granzyme B genes was associated with a shorter survival time. In addition, patients with MM had significantly more CTLs expressing perforin and granzyme B, and had an increased number of NK cells. Conclusion: Our study suggests that the gene expression profile of perforin and granzyme B is a potential prognostic marker for MM.

References

ACMG Laboratory Quality Assurance Committee. (2015). Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med, 17(5), 405-24. 10.1038/gim.2015.30.

Azuma, T., Otsuki, T., Kuzushima, K., Froelich, C. J., Fujita, S., & Yasukawa, M. (2004). Myeloma cells are highly sensitive to the granule exocytosis pathway mediated by WT1-specific cytotoxic T lymphocytes. Clin Cancer Res, 10(21), 7402-12. 10.1158/1078-0432.CCR-04-0825.

Brennan, A. J., Chia, J., Trapani, J. A., & Voskoboinik, I. (2010). Perforin deficiency and susceptibility to cancer. Cell Death Differ, 17(4), 607-15. 10.1038/cdd.2009.212.

Brown, R. D., Spencer, A., Ho, P. J., Kennedy, N., Kabani, K., Yang, S., Sze, D. M., Aklilu, E., Gibson, J., & Joshua, D. E. (2009). Prognostically significant cytotoxic T cell clones are stimulated after thalidomide therapy in patients with multiple myeloma. Leuk Lymphoma, 50(11), 1860-4. 10.3109/10428190903216804.

Cannella, S., Santoro, A., Bruno, G., Pillon, M., Mussolin, L., Mangili, G., Rosolen, A., & Aricò, M. (2007). Germline mutations of the perforin gene are a frequent occurrence in childhood anaplastic large cell lymphoma. Cancer, 109(12), 2566-71. 10.1002/cncr.22718.

Clementi, R., Locatelli, F., Dupré, L., Garaventa, A., Emmi, L., Bregni, M., Cefalo, G., Moretta, A., Danesino, C., Comis, M., Pession, A., Ramenghi, U., Maccario, R., Aricò, M., & Roncarolo, M. G. (2005). A proportion of patients with lymphoma may harbor mutations of the perforin gene. Blood, 105(11), 4424-8. 10.1182/blood-2004-04-1477.

Exome Aggregation Consortium. (2016). Analysis of protein-coding genetic variation in 60,706 humans. Nature, 536(7616), 285-91. doi: 10.1038/nature19057.

Guillerey, C., Ferrari de Andrade, L., Vuckovic, S., Miles, K., Ngiow, S. F., Yong, M. C., Teng, M. W., Colonna, M., Ritchie, D. S., Chesi, M., Bergsagel, P. L., Hill, G. R., Smyth, M. J., & Martinet, L. (2015). Immunosurveillance and therapy of multiple myeloma are CD226 dependent. J Clin Invest, 125(5), 2077-89. 10.1172/JCI77181.

Invitae Clinical Genomics Group, Topper S. (2017). Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med, 19(10), 1105-1117. 10.1038/gim.2017.37.

Ivanova, M. E., Lukoyanova, N., Malhotra, S., Topf, M., Trapani, J. A., Voskoboinik, I., & Saibil, H. R. (2022). The pore conformation of lymphocyte perforin. Science advances, 8(6), eabk3147. https://doi.org/10.1126/sciadv.abk3147.

Martínez-Pomar, N., Lanio, N., Romo, N., Lopez-Botet, M., & Matamoros, N. (2013). Functional impact of A91V mutationofthe PRF1 perforin gene. Hum Immunol, 74(1):14-7. 10.1016/j.humimm.2012.10.011.

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Published

24/10/2022

How to Cite

SOUZA, B. M. B. de .; VITO, F. B. D. .; CALADO, M. L. .; OLIVEIRA, L. R. .; SILVA, M. V. da .; RODRIGUES JÚNIOR, V. .; MORAES-HUNGRIA, V. T. de .; MORAES-SOUZA, H. . Perforin and granzyme B gene expression is associated with a short survival time in patients with multiple myeloma. Research, Society and Development, [S. l.], v. 11, n. 14, p. e111111436237, 2022. DOI: 10.33448/rsd-v11i14.36237. Disponível em: https://rsdjournal.org/index.php/rsd/article/view/36237. Acesso em: 26 nov. 2022.

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Section

Health Sciences