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Plasma Cell Disorders
Sialyltransferase inhibition leads to inhibition of tumor cell interactions with E-selectin, VCAM1, and MADCAM1, and improves survival in a human multiple myeloma
mouse model
Alessandro Natoni,1* Mariah L. Farrell,2,3,4* Sophie Harris,2,3,4
Carolyne Falank,2,3,4 Lucy Kirkham-McCarthy,1 Matthew S. Macauley,5 Michaela R. Reagan2,3,4** and Michael O’Dwyer1**
1Apoptosis Research Center, National University of Ireland, Galway, Ireland; 2Maine Medical Center Research Institute, Scarborough, ME, USA; 3Tufts University School of Medicine, Boston, MA, USA; 4Graduate School of Biomedical Science and Engineering, University of Maine, Orono, ME, USA and 5Department of Chemistry and Department of Medical Microbiology and Immunology, University of Alberta, Alberta, Canada
*AN and MLF contributed equally to this work. **MRR and MOD are joint senior authors of this work.
ABSTRACT
Aberrant glycosylation resulting from altered expression of sialyltrans- ferases, such as ST3 β-galactoside α2-3-sialyltransferase 6, plays an important role in disease progression in multiple myeloma (MM). Hypersialylation can lead to increased immune evasion, drug resistance, tumor invasiveness, and disseminated disease. In this study, we explore the in vitro and in vivo effects of global sialyltransferase inhibition on myeloma cells using the pan-sialyltransferase inhibitor 3Fax-Neu5Ac delivered as a per- acetylated methyl ester pro-drug. Specifically, we show in vivo that 3Fax-Neu5Ac improves survival by enhancing bortezomib sensitivity in an aggressive mouse model of MM. However, 3Fax-Neu5Ac treatment of MM cells in vitro did not reverse bortezomib resistance conferred by bone mar- row (BM) stromal cells. Instead, 3Fax-Neu5Ac significantly reduced interac- tions of myeloma cells with E-selectin, MADCAM1 and VCAM1, suggest- ing that reduced sialylation impairs extravasation and retention of myeloma cells in the BM. Finally, we showed that 3Fax-Neu5Ac alters the post-trans- lational modification of the α4 integrin, which may explain the reduced affinity of α4β1/α4β7 integrins for their counter-receptors. We propose that inhibiting sialylation may represent a valuable strategy to restrict myeloma cells from entering the protective BM microenvironment, a niche in which they are normally protected from chemotherapeutic agents such as borte- zomib. Thus, our work demonstrates that targeting sialylation to increase the ratio of circulating to BM-resident MM cells represents a new avenue that could increase the efficacy of other anti-myeloma therapies and holds great promise for future clinical applications.
Introduction
Multiple myeloma (MM) is characterized by clonal expansion of malignant plasma cells in the bone marrow (BM). Despite significant advances in treatment, MM remains incurable, with drug resistance mediated by the BM microenvironment being an important contributory factor.1,2 A related remarkable feature of MM is the ability for MM cells to spread from one BM site to another, which implies a persistent trafficking of circulating MM cells into and out of the BM microenvironment.3,4
Homing into the BM is physiologically governed by a diverse array of molecules such as Stromal cell-derived factor 1α (SDF1α), E-selectin, and various integrin co- receptors including Mucosal vascular addressin cell adhesion molecule 1 (MAD- CAM1).5 In the context of MM, SDF1α plays a major role in migration, adhesion, homing, and possibly retention of MM cells in the BM.6-9 Mediators of SDF1α activ-
Ferrata Storti Foundation
Haematologica 2018 Volume 105(2):457-467
Correspondence:
MICHAEL O’DWYER
michael.odwyer@nuigalway.ie
Received: November 15, 2018. Accepted: May 16, 2019. Pre-published: May 17, 2019.
doi:10.3324/haematol.2018.212266
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/457
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