Wednesday, 16 August 2017 16:22

E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271

doi: 10.1038/leu.2017.123

 

A Natoni1, T A G Smith2, N Keane1,3, C McEllistrim3, C Connolly1,3, A Jha4, M Andrulis5,6, E Ellert6, M S Raab7,8, S V Glavey1,3, L Kirkham-McCarthy1, S K Kumar9, S C Locatelli-Hoops2, I Oliva2, W E Fogler2, J L Magnani2 and M E O'Dwyer1,3

1Apoptosis Research Centre, Biomedical Sciences, National University of Ireland Galway, Galway, Ireland
2GlycoMimetics, Inc., Rockville, MD, USA
3Department of Hematology, Biomedical Sciences, National University of Ireland Galway, Galway, Ireland
4Insight Centre for Data Analytics, National University of Ireland Galway, Galway, Ireland
5Institute of Pathology, University of Ulm, Ulm, Germany
6Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
7Experimental Therapeutics for Hematologic Malignancies German Cancer Research Center (DKFZ), Heidelberg, Germany
8Department of Medicine V, Heidelberg University Medical Center, Heidelberg, Germany
9Division of Hematology, Mayo Clinic, Rochester, MN, USA

 

Abstract

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.