Gene in Stem Cell Donors May Decrease Relapse Risk in Leukemia PatientsAn analysis of patients who had undergone blood stem cell transplants for acute myelogenous leukemia (AML) suggests that certain genetic features of the donors are related to risk of AML relapse. The findings of this retrospective study show that stem cell transplants from genetically similar donors who carry a gene known as KIR2DS1, which can activate cancer-fighting natural killer (NK) cells, appear to be associated with a reduced risk of relapse in AML patients.
The study, by Drs. Katharine Hsu and Bo Dupont of Memorial Sloan-Kettering Cancer Center and their colleagues, appeared August 30 in the New England Journal of Medicine.
KIR genes code for members of a group of proteins called killer-cell immunoglobulin-like receptors, which are found on the surface of NK cells—white blood cells that can kill tumor cells.
Researchers also found that the reduced relapse rate associated with KIR2DS1 was restricted to stem cell donors with specific variants of the gene HLA-C. HLA genes code for cell-surface HLA proteins, which make up a person’s tissue type.
Hematopoietic stem cell transplants (HSCT) are given to patients who have AML to replace the diseased cells in the bone marrow with healthy stem cells that can develop into all types of blood and immune system cells to fight the leukemia. When selecting donors for HSCT, physicians match the HLA tissue type of donor and recipient to reduce the chances that the recipient’s new immune system will damage his or her other tissues and organs.
“Studies over the last 15 to 20 years have pointed to the fact that the NK cells that emerge after transplant are quite potent in destroying any remaining leukemia cells, particularly in AML,” Dr. Hsu said.
“We know that NK cells are inhibited or activated by the various KIR receptors and their interactions with HLA molecules,” she continued. “The real goal is to figure out which KIR-HLA combinations are going to allow the donor-derived NK cell to have its maximal effects in terms of leukemia control.”
The researchers examined the outcomes of HSCT in 1,277 patients with AML and 427 patients with acute lymphoblastic leukemia (ALL) who had received transplants between 1989 and 2008 from unrelated donors. The donors and recipients were matched for at least 9 of 10 possible versions of the five HLA genes. The researchers used stored blood and DNA samples to test for various types of KIR genes in stem cell donors and for HLA genes in donors and recipients.
They found that patients with AML (but not those with ALL) who received transplants from donors carrying the KIR2DS1 gene had a significantly lower risk of relapse than patients with transplants from donors without KIR2DS1. But KIR2DS1 did not improve outcomes when the donor had two copies, or alleles, of the HLA-C2 gene. This last finding is consistent with studies showing that high levels of HLA-C2 protein reduce the activity of NK cells bearing KIR2DS1 receptors.
Dr. Hsu commented that future studies should examine the effects of other KIR-HLA interactions or combinations in HSCT. “As we do this, we can become more and more refined in our donor selection criteria, with the goal of selecting a donor who is going to give the greatest benefit in terms of reducing leukemic relapse and increasing survival.”
This research was supported in part by grants from the National Institutes of Health (U01 AI69197, KL2 RR024997, R01 HL088134, and P01 CA23766).