CMV Seropositive Status Increases Heparanase SNPs Regulatory Activity, Risk of Acute GVHD and Yield of CD34+ Cell Mobilization

Abstract

Heparanase is an endo-β-glucuronidase that is best known for its pro-cancerous effects but is also implicated in the pathogenesis of various viruses. Activation of heparanase is a common strategy to increase viral spread and trigger the subsequent inflammatory cascade. Using a Single Nucleotide Polymorphisms (SNP)-associated approach we identified enhancer and insulator regions that regulate HPSE expression. Although a role for heparanase in viral infection has been noticed, the impact of HPSE functional SNPs has not been determined. We investigated the effect of cytomegalovirus (CMV) serostatus on the involvement of HPSE enhancer and insulator functional SNPs in the risk of acute graft versus host disease (GVHD) and granulocyte-colony stimulating factor related CD34+ mobilization. A significant correlation between the C alleles of insulator rs4364254 and rs4426765 and CMV seropositivity was found in healthy donors and patients with hematological malignancies. The risk of developing acute GVHD after hematopoietic stem cell transplantation was identified only in CMV-seropositive patients. A significant correlation between the enhancer rs4693608 and insulator rs28649799 and CD34+ cell mobilization was demonstrated in the CMV-seropositive donors. It is thus conceivable that latent CMV infection modulates heparanase regulatory regions and enhances the effect of functional SNPs on heparanase function in normal and pathological processes.

CMV-IgG pre-allogeneic hematopoietic stem cell transplantation and the risk for CMV reactivation and mortality

“…Interestingly, no difference in patients with low anti-CMV IgG 6-249 AU/ml (group B) and CMV seronegative (group C) was found in predicting mortality in our study. Therefore, beside the level of CMV replication, we can presume that other viral properties are likely involved in adversely affecting the prognosis of patients with higher antibody values (group A) [ 27 ]. Further studies are needed to understand the association between anti-CMV IgG levels pre-TX and late mortality.…”

Effect of HPSE and HPSE2 SNPs on the Risk of Developing Primary Paraskeletal Multiple Myeloma

“…Importantly, the discrepancy between the recipient and donor in these SNPs significantly affects the risk of acute GVHD [ 33 , 34 ]. Notably, the enhancer rs4693084 SNP and insulator rs28649799 SNP were shown to be associated with the yield of G-CSF-mediated CD34 + cell mobilization in normal donors [ 31 , 35 ]. In addition, rs4426765 is associated with heparanase gene expression in activated MNCs, as well as CD3 cell number and lymphocyte count in response to G-CSF-induced cell mobilization [ 31 ].…”