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Donor NKG2D rs1049174 polymorphism predicts hematopoietic recovery and event-free survival after single-unit cord blood transplantation in adults

Bone Marrow Transplantation volume 59, pages 566–568 (2024)Cite this article

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NKG2D (encoded by the KLRK1 gene) is a cell surface protein that belongs to the C-type lectin receptor family. It is an activating receptor in natural killer (NK) cells and a costimulatory receptor in γδ T cells, CD8+ T cells, invariant NKT cells, and some CD4+ T cells. It is involved in cell-mediated cytotoxicity and cytokine production through the blinding of ligands, including major histocompatibility complex class I polypeptide-related sequence A/B (MICA and MICB) and unique long 16-binding protein. The cytotoxic activity differs from NKG2D single nucleotide polymorphism [1]. NKG2D polymorphism rs1049174 (C > G) is a synonymous substitution positioned in the 3′ untranslated region of the KLRK1 gene. This polymorphism is implicated in the functional difference of NK cells’ cytotoxic activity by creating two different haplotype blocks: LNK1 (low-activity related, C) and HNK1 (high-activity related, G). It has been proven to influence the prevalence of cancer [1], indicating that rs1049174 polymorphism is associated with tumor immune surveillance systems through cytotoxic activity. Cord blood transplantation (CBT) is an established therapeutic option for adult patients when a human leukocyte antigen (HLA)-matched related or unrelated donor is unavailable. Although the incidence and severity of graft-versus-host disease (GVHD) after single-unit CBT is usually lower than those after conventional adult donor allogeneic hematopoietic cell transplantation (HCT), our previous study has demonstrated that CBT can induce a more potent graft-versus-leukemia (GVL) effect, leading to a lower post-transplantation relapse rate [2]. Furthermore, NK cell reconstitution is higher and more sustained after CBT compared to conventional adult donor HCT, although delayed T cell immune reconstitution is characteristic in CBT [3]. Several studies have shown the associations between donor rs1049174 and transplant outcomes, such as lower non-relapse mortality (NRM) and better overall survival (OS) in rs1049174 CG+GG donors after matched unrelated bone marrow transplantation [4], and lower relapse rate in rs1049174 CC donors after haploidentical HCT with post-transplantation cyclophosphamide (PTCy) [5]. Nevertheless, no previously published data exists on the influence of rs1049174 polymorphism on CBT. To investigate this, we examined the effect of recipient and donor NKG2D rs1049174 polymorphism on the clinical outcomes in adults who underwent CBT at our institution. NKG2D genotyping was evaluated by real-time polymerase chain reaction using TaqMan® SNP genotyping assays (Thermo Fisher Scientific, MA, USA) for rs1049174 (Applied Biosystems, CA, USA). Details for methods are provided in the Supplementary information.

Our data showed that the use of an rs1049174 CC donor was significantly associated with higher neutrophil and platelet recovery following CBT. In mice models, it is known that recipient NKG2D in NK cells prevents the engraftment of donor bone marrow grafts [6]. In humans, CD8+ T cell dose in cord blood units facilitates engraftment in single-unit CBT [7]. These data suggest that there might be an association between NKG2D and hematopoietic recovery after allogeneic HCT. Indeed, our data showed the association between donor rs1049174 CC and the facilitation of hematopoietic recovery in CBT. However, the CC allele of rs1049174 is associated with low cytotoxic activity [1]. Therefore, the opposing mechanisms underlying the association between donor rs1049174 CC and the facilitation of hematopoietic recovery have not been fully elucidated. However, it is speculated that the G allele of donor rs1049174 has the potential to increase the risk of severe pre-engraftment syndrome or pre-engraftment immune reaction, which is characterized by non-infectious fever, erythematous skin rash, and body weight gain before neutrophil engraftment. This possible phenomenon could be explained by the negative effects of hematopoietic recovery on donor rs1049174 CG + GG, which is associated with high cytotoxic activity.

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Fig. 1: CBT outcomes according to donor NKG2D gene polymorphism.

Data availability

Data may be available from the corresponding author upon reasonable request.

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Acknowledgements

The authors thank all of the physicians and staff at our hospital for their help in this study.

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Authors and Affiliations

  1. Department of Hematology/Oncology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Takaaki Konuma, Megumi Hamatani-Asakura, Maki Monna-Oiwa, Seiko Kato, Masamichi Isobe, Kazuaki Yokoyama & Yasuhito Nannya

  2. Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan

    Satoshi Takahashi

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  1. Takaaki Konuma
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Contributions

TK designed the research, performed the real-time polymerase chain reactions, analyzed the data, performed the statistical analysis, and wrote the manuscript. MHA performed the real-time polymerase chain reactions. All the other authors contributed to data collection. All authors approved the final version.

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Correspondence to Takaaki Konuma.

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The authors declare no competing interests.

Ethical approval

This study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. The Institutional Review Board of the Institute of Medical Science, University of Tokyo has approved this study (26-112-270402, 2020-1-0422).

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Konuma, T., Hamatani-Asakura, M., Monna-Oiwa, M. et al. Donor NKG2D rs1049174 polymorphism predicts hematopoietic recovery and event-free survival after single-unit cord blood transplantation in adults. Bone Marrow Transplant 59, 566–568 (2024). https://doi.org/10.1038/s41409-024-02217-2

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