What question did this study set out to answer?

The aim is to explore how donor KIR/HLA polymorphisms affect relapse risk post-transplant in T-cell malignancies.

April 19, 2026Open Access

Long-read KIR genotyping reveals donor KIR/HLA polymorphisms linked to posttransplant relapse in T-cell malignancies

Key Points

The aim is to explore how donor KIR/HLA polymorphisms affect relapse risk post-transplant in T-cell malignancies.
Conducted long-read genotyping of 15 KIR genes in 219 allo-HSCTs for adult T-cell leukemia/lymphoma.
Identified high-risk and low-risk KIR/HLA combinations through unbiased discovery analysis.
Validated findings in independent cohorts and assessed associations for amino acid-level combinations.
Identified KIR3DL1*005 or KIR3DS1*013 with HLA-B-D2-62E as high-risk combinations.
L+/H− donor combinations showed a 64% reduced relapse rate compared to L−/H+ donors.
Low-risk combinations improved overall survival rates with adjusted HR of 0.67.
KIR3DL1+ NK cells showed increased degranulation against certain targets in vitro, indicating better immune response.

Abstract

Donor polymorphisms in killer-cell immunoglobulin-like receptor (KIR) and human leukocyte antigen (HLA) shapes natural killer (NK) cell activity, which may influence relapse risk after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, comprehensive association studies have been limited by insufficient allele-level genotyping across KIR genes owing to their high sequence homology. Using high-resolution long-read genotyping of 15 KIR genes, we performed an unbiased discovery analysis in 219 allo-HSCTs for adult T-cell leukemia/lymphoma (ATL) to identify relapse-associated donor KIR/HLA polymorphisms. We tested associations for donor KIR/HLA amino acid-level combinations, accounting for linkage disequilibrium across KIR haplotypes. In addition, we validated the findings in independent cohorts. In ATL, KIR3DL1*005 or KIR3DS1*013 with glutamic acid at position 62 in the HLA-B α2 domain (HLA-B-D2-62E), or KIR3DL1*001/*007/015/*020 with HLA-B-D2-62V (valine) were identified as high-risk (H) combinations. Meanwhile, KIR3DL1*015 with isoleucine at position 80 in the HLA-B α1 domain (HLA-B-D1-80I), or KIR3DL1*001/*005/*007/*020 with HLA-B-D1-80T (threonine) were identified as low-risk (L) combinations. Compared with L−/H+ donors (N=119), L+/H−, L−/H−, and L+/H+ donors (N=80) showed reduced relapse (adjusted HR=0.36, 95% CI=0.19-0.65, P=7.5×10⁻⁴) and improved overall survival (adjusted HR=0.67, 95% CI=0.45-0.98, P=0.038). Those donors were also associated with reduced relapse in other T-cell malignancies (N=145, adjusted HR=0.37, 95% CI=0.16-0.89, P=0.026), but not in acute myeloid leukemia (N=965, P=0.77), suggesting disease specificity. Notably, low-risk combinations increased CD107a degranulation by KIR3DL1+ NK cells against HLA class I-deficient targets in vitro, consistent with enhanced NK-cell education. These findings support KIR/HLA-based donor selection and underscore the role of antitumor NK cell immunity.

Long-read KIR genotyping reveals donor KIR/HLA polymorphisms linked to posttransplant relapse in T-cell malignancies

Key Points

Abstract

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