HLA haplotype allelic variations can influence leukemia recurrence after blood stem cell transplantation

From the Petersdorf Group, Translational Science and Therapeutics Division

“Since the discovery of transplantation as a life-saving therapy for blood malignancies by Dr. E Donnall Thomas, there have been major advances that have significantly lowered the side effects and complications of the procedure itself,” explains Dr. Effie Petersdorf, a Professor in the Translational Science and Therapeutics Division and Medical Director of the Unrelated Donor Transplant Program at Fred Hutch. However, Dr. Petersdorf describes that one “high priority clinical research goal is to improve cure rates, by lowering the chances of recurrence of the patient’s underlying leukemia after transplantation.” As such, the Petersdorf research group is “interested in better understanding the nature of leukemia relapse after transplantation from the perspective of the major histocompatibility complex proteins, also known as tissue type HLA proteins.” HLA proteins are important components of the immune system and play “a fundamental role in the recognition of patient leukemia by donor T-cells,” Dr. Petersdorf adds. In their recent article published in Journal of Clinical Oncology, the Petersdorf group and colleagues “set out to better understand the role of HLA class II gene products in relapse after transplantation,” says Dr. Petersdorf.

“The group of HLA proteins known as class II includes HLA-DR and HLA-DQ molecules and are key participants in the allorecognition that leads to elimination of residual patient leukemia,” explains Dr. Petersdorf. Allorecognition refers to the immune system process in which the transplant donor recognizes different proteins, including HLA, of the patient. This recognition may lead to a complication known as graft-versus-host disease (GVHD) in the patient, but it also is an avenue for the donor cells (graft) to recognize and kill cancer cells in the transplant recipient’s body, which is known as the graft-versus-leukemia effect. Due to their crucial role, the Petersdorf team wanted to understand the clinical significance of individual HLA class II molecules and haplotypes (the specific combination of HLA alleles inherited together on a single chromosome) in leukemia relapse after blood stem cell (hematopoietic) transplantation from a haploidentical related donor. Haploidentical donors are family members who share one of their HLA haplotypes with the patient. Matching individual HLA molecules of donors and recipients is critical to reduce the risk of immune rejection of transplanted cells or tissue and GVHD, and while a perfect match would be ideal, it can be very difficult to find a match for all patients who need a transplant. Haploidentical related donors greatly expand the pool of donors for this life-saving treatment. However, even though the haploidentical related donor and recipient share one HLA haplotype, they differ for the second haplotype where even small changes in the DNA encoding these class II HLA molecules might be recognized by the donor. For each HLA haplotype, there could be thousands of tiny differences between the donor and recipient, but the question is, “which of these differences impact relapse after transplantation?” Dr. Petersdorf emphasizes that the “challenge for HLA research is how to understand the functionality of highly diverse loci, in a way that has clinical meaning.”

HLA class II genes, molecules, and haplotypes (A). Haploidentical patient and transplant donor HLA haplotypes (B). A patient and related haploidentical transplant donor share one complete HLA haplotype (gray) and are variably matched for the nonshared haplotypes (blue patient, purple donor).
HLA class II genes, molecules, and haplotypes (A). Haploidentical patient and transplant donor HLA haplotypes (B). A patient and related haploidentical transplant donor share one complete HLA haplotype (gray) and are variably matched for the nonshared haplotypes (blue patient, purple donor). Image taken from original article.

The group examined data from over 1,600 patients who received hematopoietic cell transplants from related haploidentical donors and sought to identify clinically significant allele variations on different HLA haplotypes. “We were really interested in testing the clinical importance of a particular sequence feature of HLA-DR molecules, and a novel paradigm for HLA-DQ, as a prelude to constructing extended haplotypes,” Dr. Petersdorf said. The research team investigated a specific sequence feature of HLA-DR molecules — residue 86 of the HLA-DRβ chain. This residue is said to be dimorphic as it usually encodes either a glycine (Gly) or valine (Val), which can influence the peptide-binding domain of HLA-DR molecules. “Although there has been information on the structural impact of the Gly86Val dimorphism, data regarding the clinical relevance of this feature is lacking,” Dr. Petersdorf exclaims. She continued, “we first tested the hypothesis that among haploidentical patients and transplant donors, the risks associated with HLA-DRB1 mismatching depended on whether the molecules were 86Gly or 86Val.” Consistent with their hypothesis they “learned that risks depend on the patient’s HLA-DR molecule and whether the donor has the same or different residue 86. This permitted us to simplify the definition of HLA-DR, reducing over 3588 unique DRB1 alleles to either 86Gly or 86Val.”

In addition to HLA-DR molecules, the group recently discovered that the αβ heterodimer of HLA-DQ is “a clinically relevant paradigm in unrelated donor hematopoietic cell transplantation,” as “some haplotypes permit trans-heterodimerization between one parental DQα with the opposite parental DQβ, and vice versa,” Dr. Petersdorf explains. “We tested the relevance of (mis)matching for HLA-DQ in haploidentical transplantation and discovered that the patient and donor heterodimers predicted risk of mortality for certain αβ heterodimer combinations,” which again enabled the group to reduce thousands of unique HLA-DQ alleles to a much simpler functional model. The research team extended their definition of class II haplotypes to include HLA-DM, a molecule that participates in the presentation of peptides by HLA-DR and -DQ. They discovered that haplotypes defined by all three molecules, HLA-DR, HLA-DQ and HLA-DM, provide new information on the risk of relapse.

This work enhances our understanding of how certain HLA class II genes and molecules contribute to leukemia relapse after transplantation. Here, the Petersdorf group “discovered that the risk of the recurrence of the patient’s leukemia was higher with the presence of certain haplotypes compared to others,” notes Dr. Petersdorf. She continues and explains that the “data suggest that if HLA-DR and HLA-DQ, which are currently characterized in patients and candidate donors prospectively, are visualized not simply as ‘matched’ or ‘mismatched’ allele sequences, but by what they contribute functionally at Gly86Val or as an αβ heterodimer, then we might be able to select haploidentical family members to lower the risk of leukemia recurrence.” While Petersdorf acknowledges that there is still much to understand about the role of HLA molecules in transplantation, she states, “we hope that refined approaches to the selection of donors and use of HLA information for risk prediction may contribute to improved outcomes for our patients. At the same time, it is very exciting to add to the fundamental biology of HLA genes and proteins.”


This work was supported by the National Institutes of Health, the DKMS Stigtung Leben Spenden Collaborative Research Grant and the US Office of Naval Research.

Fred Hutch/UW/Seattle Children’s Cancer Consortium members Dr. Effie Petersdorf and Dr. Ted Gooley,  contributed to this work.

Petersdorf EW, McKallor C, Malkki M, He M, Spellman SR, Gooley T, Stevenson P. HLA Haplotypes and Relapse After Hematopoietic Cell Transplantation. J Clin Oncol. 2023.

Rachel Lex

Science Spotlight writer Rachel Lex is a postdoctoral researcher in the Beronja lab at Fred Hutch. She studies what makes certain tissue regions more susceptible to cancer and looks at this from the angle of stem cell-microenvironment interactions in the skin.