Project Summary The HLA system encoded on chr6p defines the hematopoietic-cell transplantation barrier. Complete and precise HLA allele matching of the transplant donor and patient is performed to mitigate the risks of graft rejection and graft-versus-host disease. These efforts have lowered transplant-related mortality; however, relapse remains the major cause of transplant failure. The current paradigm for the HLA barrier is based on data derived principally from individual gene analyses. Yet, HLA region determinants are inherited en bloc as haplotypes, may confer risks per se, and have synergistic effects with haplotype-linked variants. The clinical significance of haplotype content or mismatching is not defined. The unmet need is an understanding of the features of HLA region genes that most strongly predict outcome, their organization on extended haplotypes, and the role of patient-donor haplotype-matching. If these principles were known, the information would improve understanding of the immunobiology of the transplant barrier, provide novel approaches for risk- assessment and optimize donor selection. We elucidated novel roles for HLA-E, HLA-B leader, MICA, MICB, - DQ heterodimers, -DM and -DO in relapse and survival after haploidentical related and unrelated donor transplantation. We have identified regional haplotypes of gene features that strongly predict outcome. These data point to a role for the extended haplotype inclusive of the chr6q ULBP complex, in transplant outcomes. The Specific Aims are to 1) define the clinical relevance of Hsp70 haplotypes; 2) define the structure and function of MICA-MICB-ULBP haplotypes; 3) determine the significance of HLA-DM-DO haplotypes in HCT and 4) define the clinical significance of long-range HLA haplotypes. The goals will be achieved through a systematic analysis of individual gene features, expression profiles, and haplotypes. We will define long-range haplotypes that most strongly predict outcome after haploidentical related donor and unrelated donor transplantation. The significance of haplotype-matching will be elucidated through the definition of haplotypes of functional features. The information from this project will significantly advance understanding of the immunogenetic transplantation barrier and offer new approaches for the reduction of relapse and improvement of survival for future patients.