The sialyltransferase ST3GAL6 influences homing and survival in multiple myeloma
Authors: Glavey, Siobhan V.; Manier, Salomon; Natoni, Alessandro; Sacco, Antonio; Moschetta, Michele; Reagan, Michaela R.; Murillo, Laura S.; Sahin, Ilyas; Wu, Ping; Mishima, Yuji; Zhang, Yu; Zhang, Wenjing; Zhang, Yong; Morgan, Gareth; Joshi, Lokesh; Roccaro, Aldo M.; Ghobrial, Irene M.; O'Dwyer, Michael E.
Glycosylation is a stepwise procedure of covalent attachment of oligosaccharide chains to proteins or lipids, and alterations in this process, especially increased sialylation, have been associated with malignant transformation and metastasis. The role of altered sialylation in multiple myeloma (MM) cell trafficking has not been previously investigated. In the present study we identified high expression of beta-galactoside alpha-2,3-sialyltransferase, ST3GAL6, in MM cell lines and patients. This gene plays a key role in selectin ligand synthesis in humans through the generation of functional sialyl Lewis X. In MRC IX patients, high expression of this gene is associated with inferior overall survival. In this study we demonstrate that knockdown of ST3GAL6 results in a significant reduction in levels of alpha-2,3-linked sialic acid on the surface of MM cells with an associated significant reduction in adhesion to MM bone marrow stromal cells and fibronectin along with reduced transendothelial migration in vitro. In support of our in vitro findings, we demonstrate significantly reduced homing and engraftment of ST3GAL6 knockdown MM cells to the bone marrow niche in vivo, along with decreased tumor burden and prolonged survival. This study points to the importance of altered glycosylation, particularly sialylation, in MM cell adhesion and migration.
A Fine-Mapping Study of 7 Top Scoring Genes from a GWAS for Major Depressive Disorder
Authors: Verbeek, Eva C.; Bakker, Ingrid M. C.; Bevova, Marianna R.; Bochdanovits, Zoltan; Rizzu, Patrizia; Sondervan, David; Willemsen, Gonneke; de Geus, Eco J.; Smit, Johannes H.; Penninx, Brenda W.; Boomsma, Dorret I.; Hoogendijk, Witte J. G.; Heutink, Peter
Major depressive disorder (MDD) is a psychiatric disorder that is characterized -amongst others- by persistent depressed mood, loss of interest and pleasure and psychomotor retardation. Environmental circumstances have proven to influence the aetiology of the disease, but MDD also has an estimated 40% heritability, probably with a polygenic background. In 2009, a genome wide association study (GWAS) was performed on the Dutch GAIN-MDD cohort. A non-synonymous coding single nucleotide polymorphism (SNP) rs2522833 in the PCLO gene became only nominally significant after post-hoc analysis with an Australian cohort which used similar ascertainment. The absence of genome-wide significance may be caused by low SNP coverage of genes. To increase SNP coverage to 100% for common variants (m.a.f > 0.1, r(2)> 0.8), we selected seven genes from the GAIN-MDD GWAS: PCLO, GZMK, ANPEP, AFAP1L1, ST3GAL6, FGF14 and PTK2B. We genotyped 349 SNPs and obtained the lowest P-value for rs2715147 in PCLO at P=6.8E-7. We imputed, filling in missing genotypes, after which rs2715147 and rs2715148 showed the lowest P-value at P=1.2E-6. When we created a haplotype of these SNPs together with the non-synonymous coding SNP rs2522833, the P-value decreased to P=9.9E-7 but was not genome wide significant. Although our study did not identify a more strongly associated variant, the results for PCLO suggest that the causal variant is in high LD with rs2715147, rs2715148 and rs2522833.