Pathogenicity and Impact of HLA Class I Alleles in Aplastic Anemia Patients of Different Ethnicities

Acquired aplastic anemia (AA) is caused by autoreactive T cell-mediated destruction of early hematopoietic cells. Somatic loss of human leukocyte antigen (HLA) class I alleles was identified as a mechanism of immune escape in surviving hematopoietic cells of some patients with AA. However, pathogenicity, structural characteristics, and clinical impact of specific HLA alleles in AA remain poorly understood. Here, we evaluated somatic HLA loss in 505 patients with AA from 2 multi-institutional cohorts. Using a combination of HLA mutation frequencies, peptide-binding structures, and association with AA in an independent cohort of 6,323 patients from the National Marrow Donor Program, we identified 19 AA risk alleles and 12 non-risk alleles and established a potentially novel AA HLA pathogenicity stratification. Our results define pathogenicity for the majority of common HLA-A/B alleles across diverse populations. Our study demonstrates that HLA alleles confer different risks of developing AA, but once AA develops, specific alleles are not associated with response to immunosuppression or transplant outcomes. However, higher pathogenicity alleles, particularly HLA-B*14:02, are associated with higher rates of clonal evolution in adult patients with AA. Our study provides insights into the immune pathogenesis of AA, opening the door to future autoantigen identification and improved understanding of clonal evolution in AA

Number of HLA-Mismatched Eplets Is Not Associated with Major Outcomes in Haploidentical Transplantation with Post-Transplantation Cyclophosphamide: A Center for International Blood and Marrow Transplant Research Study.

The number of haploidentical hematopoietic stem cell transplantations (haplo-HSCT) performed has increased substantially in recent years. Previous single-center studies using in silico algorithms to quantitively measure HLA disparity have shown an association of the number of HLA molecular mismatches with relapse protection and/or increased risk of acute graft-versus-host disease (GVHD) in haplo-HSCT. However, inconsistent results from small studies have made it difficult to understand the full clinical impact of molecular mismatch in haplo-HSCT. In this study, we investigated the potential of the HLA class I and II mismatched eplet (ME) score measured by HLAMatchmaker, as well as ME load at a specific locus to predict outcomes in a registry-based cohort of haplo-HSCT recipients. We analyzed data from 1287 patients who underwent their first haplo-HSCT for acute lymphoblastic leukemia, acute myelogenous leukemia, or myelodysplastic syndrome between 2013 and 2017, as entered in the Center for International Blood and Marrow Transplant Research database. ME load at each HLA locus and total class I and II were scored using the HLAMatchmaker module incorporated in HLA Fusion software v4.3, which identifies predicted eplets based on the crystalized HLA molecule models and identifies ME by comparing donor and recipient eplets. In the study cohort, ME scores derived from total HLA class I or class II loci or individual HLA loci were not associated with overall survival, disease-free survival, nonrelapse mortality, relapse, acute GVHD, or chronic GVHD (P < .01). An unexpected strong association was identified between total class II ME load in the GVH direction and slower neutrophil engraftment (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.75 to 0.91; P < .0001) and platelet engraftment (HR, 0.80; 95% CI, 0.72 to 0.88; P < .0001). This was likely attributable to ME load at the HLA-DRB1 locus, which was similarly associated with slower neutrophil engraftment (HR, 0.82; 95% CI, 0.73 to 0.92; P = .001) and slower platelet engraftment (HR, 0.76; 95% CI, 0.70 to 0.84; P < .0001). Additional analyses suggested that this effect is attributable to a match versus a mismatch in the graft-versus-host direction and not to ME load, as a dose effect was not identified. These findings contradict those of previous relatively small studies reporting an association between ME load, as quantified by HLAMatchmaker, and haplo-HSCT outcomes. This study failed to demonstrate the predictive value of ME from HLA molecules for major clinical outcomes, and other molecular mismatch algorithms in haplo-HSCT settings should be tested

A Receptor of the Immunoglobulin Superfamily Regulates Adaptive Thermogenesis

This work was supported by grants from the United States Public Health Service (1R01DK109675 to A.M.S. and R.R.; 1PO1HL131481 to A.M.S.; 5T32HL098129-10 to H.H.R.; and 1F31AG054129-01 to J.D.); the American Diabetes Association (1-15-MI-14 to C.H.d.P.); and the American Heart Association (17SFRN33520045 to A.M.S. and H.H.R.). Part of this work was funded by Research Funds of the Diabetes Research Program at NYU (to A.M.S. and R.R.). The Experimental Pathology Research Laboratory is partially funded by the Cancer Center Support grant P30CA016087 at NYU Langone’s Cancer Center. Part of this work was funded by the National Mouse Metabolic Phenotyping Center at UMass funded by NIH grant 5U2C-DK093000 (to J.K.K.).Exquisite regulation of energy homeostasis protects from nutrient deprivation but causes metabolic dysfunction upon nutrient excess. In human and murine adipose tissue, the accumulation of ligands of the receptor for advanced glycation end products (RAGE) accompanies obesity, implicating this receptor in energy metabolism. Here, we demonstrate that mice bearing global- or adipocyte-specific deletion of Ager, the gene encoding RAGE, display superior metabolic recovery after fasting, a cold challenge, or high-fat feeding. The RAGE-dependent mechanisms were traced to suppression of protein kinase A (PKA)-mediated phosphorylation of its key targets, hormone-sensitive lipase and p38 mitogen-activated protein kinase, upon β-adrenergic receptor stimulation—processes that dampen the expression and activity of uncoupling protein 1 (UCP1) and thermogenic programs. This work identifies the innate role of RAGE as a key node in the immunometabolic networks that control responses to nutrient supply and cold challenges, and it unveils opportunities to harness energy expenditure in environmental and metabolic stress.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEpu

HLA Class I genotype is associated with relapse risk after allogeneic stem cell transplantation for NPM1-mutated AML

•In an 8/8 matched transplant cohort, several HLA Class I alleles were predicted to have strong binding to mutated NPM1 peptides•Presence of predicted strong binding alleles was associated with a lower risk of post-transplant relapse Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA Class I in acute myeloid leukemia (AML). We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes in NPM1-mutated AML due to differences in antigen presentation. We evaluated the effect of the variable of predicted strong binding to mutated NPM1 peptides using HLA Class I genotypes from matched donor:recipient pairs on transplant recipient overall survival (OS) and disease free survival (DFS) as part of primary objectives, and relapse risk (CIR) and non-relapse mortality (NRM) as part of secondary objectives. Study Design: Baseline and outcome data reported to the Center for International Blood and Marrow Transplant Research from a study cohort of adult patients (N=1020) with NPM1-mutated de novo AML in first (71%) or second (29%) complete remission undergoing 8/8 matched related (18%) or matched unrelated (82%) allo-HCT were retrospectively analyzed. Class I alleles from donor:recipient pairs were analyzed for predicted strong HLA binding to mutated NPM1 using netMHCpan 4.0. 429 (42%) of donor:recipient pairs were classified as having predicted strong binding HLA alleles (SBHA) to mutated NPM1. In multivariable analyses adjusting for clinical covariates, the presence of predicted SBHA was associated with a lower risk of relapse (HR 0.72, 95% CI 0.55-0.94, p=0.015). Overall survival (HR 0.81, 95% CI 0.67-0.98, p=0.028) and DFS (HR 0.84, 95% CI 0.69-1.01, p=0.070) had a suggestion towards better outcomes if predicted SBHA were present but did not meet prespecified p<0.025. Non-relapse mortality did not differ (HR 1.04, p=0.740). These hypothesis generating data support further exploration of HLA genotype:neoantigen interactions in the allo-HCT context

HLA Class I Genotype Is Associated with Relapse Risk after Allogeneic Stem Cell Transplantation for NPM1-Mutated Acute Myeloid Leukemia

Mutation-bearing peptide ligands from mutated nucleophosmin-1 (NPM1) protein have been empirically found to be presented by HLA class I in acute myeloid leukemia (AML). We hypothesized that HLA genotype may impact allogeneic hematopoietic stem cell transplantation (allo-HCT) outcomes in NPM1-mutated AML owing to differences in antigen presentation. We evaluated the effect of the variable of predicted strong binding to mutated NPM1 peptides using HLA class I genotypes from matched donor-recipient pairs on transplant recipients’ overall survival (OS) and disease-free survival (DFS) as part of the primary objectives and cumulative incidence of relapse and nonrelapse mortality (NRM) as part of secondary objectives. Baseline and outcome data reported to the Center for International Blood and Marrow Transplant Research from a study cohort of adult patients (n = 1020) with NPM1-mutated de novo AML in first (71%) or second (29%) complete remission undergoing 8/8 matched related (18%) or matched unrelated (82%) allo-HCT were analyzed retrospectively. Class I alleles from donor-recipient pairs were analyzed for predicted strong HLA binding to mutated NPM1 using netMHCpan 4.0. A total of 429 (42%) donor-recipient pairs were classified as having predicted strong-binding HLA alleles (SBHAs) to mutated NPM1. In multivariable analyses adjusting for clinical covariates, the presence of predicted SBHAs was associated with a lower risk of relapse (hazard ratio [HR],.72; 95% confidence interval [CI],.55 to.94; P =.015). OS (HR,.81; 95% CI,.67 to.98; P =.028) and DFS (HR,.84; 95% CI,.69 to 1.01; P =.070) showed a suggestion of better outcomes if predicted SBHAs were present but did not meet the prespecified P value of <.025. NRM did not differ (HR, 1.04; P =.740). These hypothesis-generating data support further exploration of HLA genotype-neoantigen interactions in the allo-HCT context