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Principal Investigator: Effie W Petersdorf
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $421,457
Funding agency: National Cancer Institute
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.
Terms: <Acute><African><Alleles><Allelomorphs><Allogenic><Area><Asian><Binding><Biological><Blood Diseases><CTX><CYCLO-cell><Carloxan><Caucasian><Caucasian Race><Caucasians><Caucasoid><Caucasoid Race><Cell Body><Cells><Chaperone><Chronic><Ciclofosfamida><Ciclofosfamide><Cicloxal><Clafen><Claphene><Clinical><Complex><Cord Blood Transplantation><Cycloblastin><Cycloblastine><Cyclophospham><Cyclophosphamide><Cyclophosphamidum><Cyclophosphan><Cyclophosphane><Cyclophosphanum><Cyclostin><Cyclostine><Cytophosphan><Cytophosphane><Cytoxan><Data><Disease-Free Survival><Donor Screening><Donor Selection><Donor person><Endoxan><Endoxana><Enduxan><Equilibrium><Ethnic Origin><Ethnicity><Event-Free Survival><Failure><Fosfaseron><Future><Genes><Genoxal><Genuxal><Germ Lines><Goals><Graft Rejection><GvHD><HLA-B><HLA-B Antigens><HLA-DC><HLA-DC Antigens><HLA-DQ><HLA-DQ Antigens><HLA-DS><HLA-DS Antigens><HLA-LB><HLA-LB Antigens><HLA-MB><HLA-MB Antigens><HSC transplantation><Haplotypes><Hematologic Diseases><Hematological Disease><Hematological Disorder><Hematopoietic Stem Cell Transplant><Hematopoietic Stem Cell Transplantation><Hereditary><Hispanic><Homologous Wasting Disease><Human Genome><Immune response><Immune system><Immunobiology><Immunogenetics><Immunological response><Immunophysiology><Individual><Inherited><Leader Peptide><Leader Signal Peptide><Ledoxina><Ligands><Link><Malignant><Malignant - descriptor><Maps><Methods><Mica><Mitoxan><Modeling><Molecular Chaperones><Molecular Interaction><Monitor><Morbidity><Morbidity - disease rate><Neosar><Occidental><Outcome><Parents><Pathway interactions><Patients><Peptide Leader Sequences><Peptides><Phase><Play><Population Heterogeneity><Procytox><Progenitor Cells><Proteins><Race><Races><Regimen><Relapse><Risk><Risk Assessment><Role><Runt Disease><Sendoxan><Shapes><Source><Structure><Syklofosfamid><System><Translations><Transplant Recipients><Transplant Rejection><Transplant-Related Disorder><Transplantation><Transplantation Rejection><UCB transplantation><Umbilical Cord Blood Transplantation><Variant><Variation><Zytoxan><balance><balance function><biologic><blood disorder><clinical relevance><clinical significance><clinically relevant><clinically significant><conditioning><customized therapy><customized treatment><diverse populations><graft failure><graft versus host disease><graft vs host disease><graft vs. host disease><hematopoietic cell transplantation><hematopoietic cellular transplantation><hematopoietic progenitor cell transplantation><heterogeneous population><high risk><host response><human whole genome><immune system response><immunoresponse><improved><improved outcome><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><mortality><new approaches><novel><novel approaches><novel strategies><novel strategy><outcome prediction><parent><pathway><patient specific therapies><patient specific treatment><population diversity><post-transplant><post-transplantation><posttransplant><posttransplantation><racial><racial background><racial diversity><racial origin><racially diverse><relapse risk><risk mitigation><social role><stem cells><survivorship><synergism><tailored medical treatment><tailored therapy><tailored treatment><translation><transplant><transplant disease><transplant donor><transplant patient><unique treatment><white race>