Comparative analysis of the variability of the human leukocyte antigen peptide‐binding pockets in patients with acute leukaemia

Abstract

Summary The association between acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) and the human leukocyte antigens (HLA) has rarely been studied in terms of diversity of peptide‐binding pockets. The objective of this study was to analyse whether motifs of HLA class I and class II peptide‐binding pockets and/or their amino acid positions were differentially associated with ALL and AML. We included 849 patients from the Eurocord/European Blood and Marrow Transplant registry. The HLA peptide‐binding pockets whose amino acid variability was analysed were B and F for HLA class I, P4, P6, and P9 for HLA‐DRB1, and P4 and P9 for HLA‐DQB1. The motif RFDRAY in P4 of HLA‐DRB1*16:01/02/03/05 alleles and the motif YYVSY in P9 of HLA‐DQB1*05:02/04/05 alleles, were statistically associated with ALL (corrected p value [pc] = 0.001 and pc = 0.035 respectively). The frequency of serine 57 in the P9 of HLA‐DQB1 was higher in ALL (odds ratio 2.09, 95% confidence interval: 1.27–3.44; pc = 0.037). Our analysis suggests that specific motifs in terms of HLA class II pockets and amino acids might be unique to ALL. The associations identified in this study encourage further investigation oF the role of HLA peptide‐binding pockets and their amino acids in immune processes underpinning acute leukaemia and ultimately in immunotherapy settings.

Digging into the HLA pockets: A new association with acute leukaemias

“…Importantly, only motifs belonging to class II HLA (DQB1, DRB1) pockets were characteristically associated with ALL in this study 6 . Analogies to previous reports on specific class II HLA alleles and human pathology of an autoimmune nature and cancer are obvious and warrant further studies.…”

“…Importantly, only motifs belonging to class II HLA (DQB1, DRB1) pockets were characteristically associated with ALL in this study. 6 Analogies to previous reports on specific class II HLA alleles and human pathology of an autoimmune nature and cancer are obvious and warrant further studies. A recent work on HLA evolutionary divergence (HED), a new metric that can be considered as an indirect measure of the breadth of the human immunopeptidome, found that lower class II HED imprinted a higher risk of leukaemic progression in patients with acquired aplastic anaemia.…”

“…In this issue, Boukouaci et al 6 took advantage of the Eurocord/European Blood and Marrow Transplant (EBMT) registry to explore the patterns of distribution of specific HLA motifs in a retrospective cohort of 849 patients with ALL ( n = 426) and AML ( n = 423) who had undergone HSCT from umbilical cord blood between 2001 and 2018. The authors found that a specific motif in P4 of the HLA DRB1*16:01/02/03/05 alleles (RFDRAY) was associated with acute leukaemias of lymphoid lineage (Figure 1 ).…”

HLA peptide‐binding pocket diversity modulates immunological complications after cord blood transplant in acute leukaemia

“…13 Some studies have demonstrated the implication of specific positions and/or pockets within peptide-binding regions in the risk to develop immune-related disorders, as these pockets within certain HLA molecules possess a pivotal role in the selection and stability of antigenic peptides. 14,15 We deciphered the HLA peptide-binding diversity in acute myeloid leukaemia (AML) and acute lymphoblastic leukaemia (ALL), demonstrating the relationship between specific HLA class II motifs in ALL, but not in AML, and suggesting an HLA-mediated differential risk for both types of leukaemia. 15 Therefore, the objective of this study was to analyse whether HLA amino acid pockets constituting the peptide-binding grooves of HLA class I HLA-A, -B and -C (B and F pockets) and HLA class II -DRB1 (P4, P6 and P9) and -DQB1 (P4 and P9) were associated with post-UCBT outcomes in patients with acute leukaemia.…”

“…Within the HLA class II molecules, five pockets (P1, P4, P6, P7 and P9) govern peptide management 13 . Some studies have demonstrated the implication of specific positions and/or pockets within peptide‐binding regions in the risk to develop immune‐related disorders, as these pockets within certain HLA molecules possess a pivotal role in the selection and stability of antigenic peptides 14,15 …”