# Clinical Significance of MHC Haplotypes in HCT

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2024 · $421,457

## Abstract

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.

## Key facts

- **NIH application ID:** 10931530
- **Project number:** 5R01CA100019-23
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Effie W Petersdorf
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $421,457
- **Award type:** 5
- **Project period:** 2003-03-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10931530

## Citation

> US National Institutes of Health, RePORTER application 10931530, Clinical Significance of MHC Haplotypes in HCT (5R01CA100019-23). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10931530. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*