NFKB1 gene single-nucleotide polymorphisms: implications for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation

Abstract

Graft-versus-host disease (GVHD) represents a significant cause of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). NF-kB system is a master regulator of innate immunity responses. It controls the expression of various cytokines and chemokines many of which are involved in GVHD pathogenesis. Chemo(radio) therapy administered during conditioning induces DNA damage and activates DNA damage response (DDR) signaling resulting in irreversible cell cycle arrest – cellular senescence which has been described to be associated with robust pro-inflammatory secretion mostly controlled by NF-kB. The NFKB1 gene encodes the DNA-binding subunit of the NF-kB complex. Using the candidate gene approach, we analyzed possible association of two single-nucleotide polymorphisms (SNPs) rs3774937 C/T and rs3774959 A/G of the NFKB1 gene with GVHD and transplant-related mortality (TRM) occurrence in 109 recipients allografted from HLA-identical donor. Both SNPs in recipients were found to be strongly associated with acute GVHD. Nevertheless, no significant association with chronic GVHD and TRM was found. Presented pilot results contribute to pre-clinical observations and suggest that NF-kB may be an important regulator of HSCT-related inflammatory reactions such as acute GVHD. Novel pathogenic mechanisms of GVHD may arise from perspectives of DDR and cellular senescence where NF-kB plays an essential role.

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Funding

This study was funded by MHCZ-DRO (FNOl, 00098892), IGA_LF_2019_001.

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Correspondence to Adam Kuba.

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Kuba, A., Raida, L., Mrazek, F. et al. NFKB1 gene single-nucleotide polymorphisms: implications for graft-versus-host disease in allogeneic hematopoietic stem cell transplantation. Ann Hematol 99, 609–618 (2020). https://doi.org/10.1007/s00277-020-03935-5

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Keywords

  • Allogeneic hematopoietic stem cell transplantation
  • Graft-versus-host disease
  • Single-nucleotide polymorphism
  • NFKB1 gene
  • Cellular senescence
  • Senescence-associated secretory phenotype