TY - JOUR
T1 - E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271
AU - Natoni, A.
AU - Smith, T. A.G.
AU - Keane, N.
AU - McEllistrim, C.
AU - Connolly, C.
AU - Jha, A.
AU - Andrulis, M.
AU - Ellert, E.
AU - Raab, M. S.
AU - Glavey, S. V.
AU - Kirkham-Mccarthy, L.
AU - Kumar, S. K.
AU - Locatelli-Hoops, S. C.
AU - Oliva, I.
AU - Fogler, W. E.
AU - Magnani, J. L.
AU - O'dwyer, M. E.
N1 - Publisher Copyright:
© The Author(s) 2017.
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85038254185&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85038254185&partnerID=8YFLogxK
U2 - 10.1038/LEU.2017.123
DO - 10.1038/LEU.2017.123
M3 - Article
C2 - 28439107
AN - SCOPUS:85038254185
SN - 0887-6924
VL - 31
SP - 2642
EP - 2651
JO - Leukemia
JF - Leukemia
IS - 12
ER -