Life-threatening risks associated with HLA-mismatched unrelated donor hematopoietic cell transplantation (HCT) limit its general application for the treatment of blood diseases. In CA100019, we have taken a haplotype approach to investigate the MHC as a source of untyped variation. We mapped haplotype effects of acute or chronic graft-versus-host disease (GVHD), relapse, or mortality after HLA-mismatched unrelated donor HCT to 12 single nucleotide polymorphisms (SNPs). SNP-associated risks were conferred by either patient or donor genotype or by patient-donor mismatching. Risks after transplantation increased with increasing numbers of unfavorable SNPs. SNPs affected acute GVHD independently from chronic GVHD. SNPs also lowered relapse independently of GVHD. Haplotype-specific content for candidate genes can be used clinically to assess risks in patients and to select donors with optimal MHC genetics.
The aims of CA100019 are to: 1) confirm the impact of the 12 SNPs in HLA-mismatched transplants;2) determine the content of homozygous HLA haplotypes for candidate transplant genes;3) identify specific polymorphisms associated with risks after mismatched unrelated HCT, and 4) identify risks associated with HLA mismatches. CA100019 will contribute novel information on the genes and putative pathways involved in GVHD and graft- versus-leukemia, and provide clinicians with a haplotype-based approach for optimizing HLA-mismatched unrelated donor HCT.

Public Health Relevance

We are discovering the genes that are responsible for the success of blood and marrow transplantation from unrelated donors. Information on these genes will help physicians to choose better donors and to lower risks for patients who need a transplant to cure diseases of the blood system.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA100019-11
Application #
8576359
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Merritt, William D
Project Start
2003-03-01
Project End
2018-05-31
Budget Start
2013-08-07
Budget End
2014-05-31
Support Year
11
Fiscal Year
2013
Total Cost
$336,873
Indirect Cost
$145,468
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; O'hUigin, Colm et al. (2015) High HLA-DP Expression and Graft-versus-Host Disease. N Engl J Med 373:599-609
Petersdorf, Effie W (2015) HLA mismatching in transplantation. Blood 125:1058-9
Pidala, Joseph; Lee, Stephanie J; Ahn, Kwang Woo et al. (2014) Nonpermissive HLA-DPB1 mismatch increases mortality after myeloablative unrelated allogeneic hematopoietic cell transplantation. Blood 124:2596-606
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Israeli, Moshe; Roelen, Dave L; Carrington, Mary et al. (2014) Association between CTL Precursor Frequency to HLA-C Mismatches and HLA-C Antigen Cell Surface Expression. Front Immunol 5:547
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