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

• Published in: Leukemia Vol. 31; no. 12; pp. 2642 - 2651
• Main Authors: Natoni, A, Smith, T A G, Keane, N, McEllistrim, C, Connolly, C, Jha, A, Andrulis, M, Ellert, E, Raab, M S, Glavey, S V, Kirkham-McCarthy, L, Kumar, S K, Locatelli-Hoops, S C, Oliva, I, Fogler, W E, Magnani, J L, O'Dwyer, M E
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-12-2017; Nature Publishing Group
• Subjects: 13/106; 13/31; 13/51; 13/62; 14/34; 631/45/612/1237; 631/67/1059/99; 631/67/1990/804; 64/60; 692/4028/67/1059/602; 692/699/67/1059/2326; Animals; Bone marrow; Bortezomib; Bortezomib - pharmacology; Cancer cells; Cancer Research; Care and treatment; Cell Adhesion; Cell Survival - drug effects; Chemoresistance; Chemotherapy; Critical Care Medicine; Diagnosis; Disease Models, Animal; Drug resistance; Drug Resistance, Neoplasm - drug effects; E-selectin; E-Selectin - antagonists & inhibitors; E-Selectin - metabolism; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glycoproteins; Hematology; Homing; In vivo methods and tests; Intensive; Internal Medicine; Ligands; Medicine; Medicine & Public Health; Metastases; Mice; Microvasculature; mRNA; Multiple myeloma; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - mortality; Multiple Myeloma - pathology; Oncology; Original; original-article; Peripheral blood; Plasma cells; Prognosis; Protein Binding; Recurrence; Shear stress; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2017.123

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.