PF756 DONOR UNC-93 HOMOLOG B1 GENETIC VARIATION PREDICTS SURVIVAL OUTCOMES AFTER UNRELATED BONE MARROW TRANSPLANTATION
Authors: K. Uchino, S. Mizuno, T. Horio, M. Mizutani, A. Nakamura, S. Takasugi, I. Hanamura, L. Vu, Y. Kodera, J.L. Espinoza, M. Onizuka, K. Kashiwase, Y. Morishima, T. Fukuda, N. Doki, K. Miyamura, T. Mori, E. Morishita, S. Nakao, A. Takami
Journal: HemaSphere (2019)

Background: The toll-like receptors (TLRs) are the most important pattern recognition receptors that sense invading pathogens and mount innate and adaptive immune response. TLRs are also suggested to contribute to the inflammatory process after allogeneic stem cell transplantation (allo-SCT). Unc-93 homolog B1 (UNC93B1) is a key regulator of TLRs and delivers them from the endoplasmic reticulum to their respective endosomal signaling compartments. UNC93B is encoded by the UNC93B1 gene on chromosome 11q13 and has one important single-nucleotide polymorphism (SNP) rs308328 (T>C) in an intronic region that is functional, and the major allele (T) has been reported to be associated with lower UNC93B1 expression. We therefore hypothesized that the UNC93B1 rs308328 might be associated with clinical outcomes after allo-SCT. Aims: We investigated the influence of the UNC93B1 SNP on transplant outcomes in a cohort of patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program (JMDP). Methods: The UNC93B1 genotyping was performed on 237 transplant recipients, including 109 with acute myeloid leukemia (AML; 46%), 57 with acute lymphoblastic leukemia (ALL; 24%), 37 with myelodysplastic syndrome (MDS; 16%), 10 with chronic myeloid leukemia (CML; 4%), and 24 with malignant lymphoma (ML; 10%), and their unrelated donors who underwent BMT through the JMDP with T cell-replete marrow from HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DQB1 and HLA-DPB1 allele-matched donors between January 2006 and December 2009. We retrospectively examined the impact of the UNC93B1 SNP on transplant outcomes. Results: The genotype frequencies of C/C, C/T, and T/T in the UNC93B1 SNP were 14%, 40% and 46% in the donors and 14%, 40% and 46% in the recipients (P = 0.98), respectively. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival (OS) than the donor UNC93B1 C/T or T/T genotype (77% vs. 58%; P = 0.040; Fig. 1). The donor UNC93B1 C/C genotype also exhibited a trend toward a lower 3-year transplant-related mortality (14% vs. 27%, P = 0.073) but did not reduce the 3-year relapse rate (13% vs. 17%, P = 0.72). The donor UNC93B1 C/C genotype remained associated with a better 3-year OS (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.18–0.97; P = 0.043) than the donor UNC93B1 C/T or T/T genotype in the multivariate analysis.Summary/Conclusion: The current study showed that the donor UNC93B1 rs308328 C/C genotype, which putatively has higher inducibility of UNC93B1 than the UNC93B1 rs308328 C/T or T/T genotype, was associated with a better OS in patients with hematologic malignancies receiving unrelated BMT than the donor UNC93B1 rs308328 C/T or T/T genotype. An analysis of the UNC93B1 genotype could therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allo-SCT, such as alterations in the in vivo regulation of the UNC93B1 gene.