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

A. Natoni, T. A.G. Smith, N. Keane, C. McEllistrim, C. Connolly, A. Jha, M. Andrulis, E. Ellert, M. S. Raab, S. V. Glavey, L. Kirkham-McCarthy, Shaji K Kumar, S. C. Locatelli-Hoops, I. Oliva, W. E. Fogler, J. L. Magnani, M. E. O'Dwyer

Research output: Contribution to journalArticle

7 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)2642-2651
Number of pages10
JournalLeukemia
Volume31
Issue number12
DOIs
StatePublished - Dec 1 2017

Fingerprint

E-Selectin
Drug Resistance
Ligands
Multiple Myeloma
Bone Marrow
Sialyltransferases
Microvessels
Plasma Cells
Disease-Free Survival
Neoplasm Metastasis
Cell Line
Messenger RNA

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine

Cite this

Natoni, A., Smith, T. A. G., Keane, N., McEllistrim, C., Connolly, C., Jha, A., ... O'Dwyer, M. E. (2017). E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271. Leukemia, 31(12), 2642-2651. https://doi.org/10.1038/leu.2017.123

E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271. / 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, Shaji K; Locatelli-Hoops, S. C.; Oliva, I.; Fogler, W. E.; Magnani, J. L.; O'Dwyer, M. E.

In: Leukemia, Vol. 31, No. 12, 01.12.2017, p. 2642-2651.

Research output: Contribution to journalArticle

Natoni, A, Smith, TAG, Keane, N, McEllistrim, C, Connolly, C, Jha, A, Andrulis, M, Ellert, E, Raab, MS, Glavey, SV, Kirkham-McCarthy, L, Kumar, SK, Locatelli-Hoops, SC, Oliva, I, Fogler, WE, Magnani, JL & O'Dwyer, ME 2017, 'E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271', Leukemia, vol. 31, no. 12, pp. 2642-2651. https://doi.org/10.1038/leu.2017.123
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, Shaji K ; Locatelli-Hoops, S. C. ; Oliva, I. ; Fogler, W. E. ; Magnani, J. L. ; O'Dwyer, M. E. / E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271. In: Leukemia. 2017 ; Vol. 31, No. 12. pp. 2642-2651.
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AU - McEllistrim, C.

AU - Connolly, C.

AU - Jha, A.

AU - Andrulis, M.

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AU - Kumar, Shaji K

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