Single-Nucleotide Polymorphisms in MICA and MICB Genes Could Play a Role in the Outcome in AML Patients after HSCT

Abstract

NKG2D and its ligands, MICA and MICB, are known as the key regulators of NK cells. NK cells are the first reconstituted cells after the allogeneic hematopoietic stem cell transplantation (HSCT); therefore, it is crucial to understand their role in HSCT outcome. In the presented study, we investigated the single amino acid changes across the exons 2–4 of MICA and MICB genes, and point mutations within the NKG2D gene, which defines the type of NKG2D haploblock (HNK/LNK) in the donors (n = 124), as well as in patients with acute myeloid leukemia (n = 78). In our cohort, we found that graft from a donor with at least one MICA allele containing glycine at position 14 (MICA-14Gly) is significantly associated with deterioration of a patient’s overall survival (OS) (p < 0.05). We also observed a negative effect of MICB-58 (Lys → Glu) polymorphism on relapse-free survival (RFS), although it was not statistically significant in multivariate analysis (p = 0.069). To our knowledge, this is the first work describing the role of MICA-14 and MICB-58 polymorphisms on HSCT outcome.

Role of NKG2D ligands and receptor in haploidentical related donor hematopoietic cell transplantation

“…15 , 16 MICB missense changes were selected based on 3 criteria: (1) a frequency of 3% or higher in 1000 Genomes Black, Asian, White, and Hispanic populations; 47 (2) missense proxies had a global r 2 of 0.75 or higher, and (3) missense change has potential biological relevance. 37 , 38 , 48 , 49 , 50 Four MICB residues met all criteria (residues 52, 57, 98, and 189). MICA-STR, MICA-129 (rs1051792), MICB-52 (rs3131639), MICB-57 (rs1065075), MICB-98 (rs3134900), MICB-189 (rs41293883), and NKG2D-72 (rs2255336) were characterized as described ( supplemental Methods ; supplemental Table 2 ).…”

“… 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 No information on the effect of MICA-STR on the transplantation outcome is available despite its strong effects on expression. 18 , 20 , 21 , 22 , 23 New evidence implicates the mismatch of specific MICB residues and NKG2D cytotoxicity haplotypes in the transplantation outcome, 37 , 38 , 39 but an understanding of the combined effects of the receptor and its ligands is lacking.…”

Identification of a novel MICB allele, MICB*014:02, by cloning and sequencing

“…The human major histocompatibility complex (MHC) class I chain‐related gene B ( MICB gene) is a non‐classical MHC class I gene. Polymorphisms of the MICB gene have been found to be associated with the susceptibility of some diseases and the outcome of hematopoietic stem cell transplantation (HSCT) 1–4 . Currently, 244 MICB alleles have been officially named and are available in the IPD‐IMGT/HLA Database 5 .…”

“…Polymorphisms of the MICB gene have been found to be associated with the susceptibility of some diseases and the outcome of hematopoietic stem cell transplantation (HSCT). [1][2][3][4] Currently, 244 MICB alleles have been officially named and are available in the IPD-IMGT/HLA Database. 5 In this article, we describe a novel MICB allele, now officially named MICB*014:02, which was identified by Sanger sequencing and confirmed by cloning and sequencing in a Chinese hematopoietic stem cell donor.…”

The impact of NKG2A and NKG2D receptors and HLA-E and MICA ligands polymorphisms on post-transplant complications after paediatric allogeneic HSCT: a single-centre experience

“…There have been a number of studies suggesting some associations of polymorphisms within genes coding for NKG2 receptor ligands and the transplant outcome in adult HSCT recipients (sometimes with inconsistent results), but-to Frontiers in Genetics frontiersin.org the best of our knowledge-none of them investigated paediatric patients subjected to the allogeneic HSCT procedure [reviewed in Partanen et al (2020) and Bogunia-Kubik and Łacina (2021)]. One of the selected SNPs, the NKG2A rs7301582, has not been investigated in HSCT settings.…”