The long-term goals of CA100019 are to improve the outcome of unrelated donor (URD) hematopoietic cell transplantation (HCT) and broaden the application of mismatched HCT through a better understanding of the immunogenetics of the transplantation barrier. We hypothesize that undetected variation within the gene- dense MHC could contribute to risks after HLA-matched and HLA-mismatched URD HCT. We developed a novel long-range phasing method to link HLA alleles in unrelated individuals and demonstrated that haplotype mismatching is associated with higher risk of clinically severe acute graft-versus-host disease (GVHD) after HLA matched and HLA mismatched HCT. Patients mismatched for both HLA alleles and haplotypes had significantly lower survival. Haplotype-mismatched donors and recipients had a greater degree of disparity for MHC-resident variation compared to haplotype-matched pairs, and undetected disparity was associated with increased post-transplant risks. These data demonstrate that the haplotype is a proxy for transplant risk. To define the risks of GVHD, relapse, TRM and mortality in a larger independent clinical transplant population, we will refine our long-range phasing method and develop short-range phasing methods to map variation (Specific Aim 1). We will determine the extent to which haplotype matching can lower risks of GVHD and TRM, while preserving graft-versus-leukemia effects (Specific Aim 2). We will identify novel MHC-resident variation associated with transplant risks (Specific Aim 3). CA100019 will provide a powerful practical immunogenetic approach for optimizing URD HCT and for broadening the use of HLA mismatched URDs. Finally, CA100019 will contribute novel genetic data needed for hypothesis-driven and exploratory gene mapping.

Public Health Relevance

We developed a tool for studying human chromosomes and genes, and discovered ways to improve the results of unrelated transplantation for the treatment of blood disorders. We will use the tool to find the genes that are important to transplant success.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA100019-10
Application #
8212577
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Wu, Roy S
Project Start
2008-03-04
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$334,184
Indirect Cost
$144,306
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
078200995
City
Seattle
State
WA
Country
United States
Zip Code
98109
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Petersdorf, Effie W; Malkki, Mari; Horowitz, Mary M et al. (2013) Mapping MHC haplotype effects in unrelated donor hematopoietic cell transplantation. Blood 121:1896-905
Petersdorf, Effie W (2013) Genetics of graft-versus-host disease: the major histocompatibility complex. Blood Rev 27:1-12
Moran, D; Morishima, S; Malkki, M et al. (2013) Identification of the MICA*070 allele by sequencing and phasing. Hum Immunol 74:557-61
Morishima, Yasuo; Kawase, Takakazu; Malkki, Mari et al. (2013) Significance of ethnicity in the risk of acute graft-versus-host disease and leukemia relapse after unrelated donor hematopoietic stem cell transplantation. Biol Blood Marrow Transplant 19:1197-203
Petersdorf, Effie W (2013) The major histocompatibility complex: a model for understanding graft-versus-host disease. Blood 122:1863-72
Woolfrey, Ann; Klein, John P; Haagenson, Michael et al. (2011) HLA-C antigen mismatch is associated with worse outcome in unrelated donor peripheral blood stem cell transplantation. Biol Blood Marrow Transplant 17:885-92
Walter, R B; Pagel, J M; Gooley, T A et al. (2010) Comparison of matched unrelated and matched related donor myeloablative hematopoietic cell transplantation for adults with acute myeloid leukemia in first remission. Leukemia 24:1276-82
Petersdorf, E W (2010) The World Marrow Donor Association: 20 years of international collaboration for the support of unrelated donor and cord blood hematopoietic cell transplantation. Bone Marrow Transplant 45:807-10
Ringden, Olle; Pavletic, Steven Z; Anasetti, Claudio et al. (2009) The graft-versus-leukemia effect using matched unrelated donors is not superior to HLA-identical siblings for hematopoietic stem cell transplantation. Blood 113:3110-8

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