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Upregulated expression and function of the α 4 β 1 integrin in multiple myeloma cells resistant to bortezomib
Author(s) -
SevillaMovilla Silvia,
ArellanoSánchez Nohemí,
MartínezMoreno Mónica,
Gajate Consuelo,
SánchezVencells Anna,
Valcárcel Luis V,
Agirre Xabier,
Valeri Antonio,
MartínezLópez Joaquin,
Prósper Felipe,
Mollinedo Faustino,
Teixidó Joaquin
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5480
Subject(s) - bortezomib , downregulation and upregulation , proteasome inhibitor , integrin , cancer research , multiple myeloma , cell growth , cell adhesion , cell , bone marrow , apoptosis , biology , microbiology and biotechnology , immunology , biochemistry , gene
The interaction of multiple myeloma (MM) cells with the bone marrow (BM) microenvironment promotes MM cell retention, survival, and resistance to different anti‐MM agents, including proteasome inhibitors (PIs) such as bortezomib (BTZ). The α4β1 integrin is a main adhesion receptor mediating MM cell–stroma interactions and MM cell survival, and its expression and function are downregulated by BTZ, leading to inhibition of cell adhesion‐mediated drug resistance (CAM‐DR) and MM cell apoptosis. Whether decreased α4β1 expression and activity are maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of α4β1 function could boost MM cell survival and disease progression. Using BTZ‐resistant MM cells, we found that they not only rescue their α4β1 expression, but its levels were higher than in parental cells. Increased α4β1 expression in resistant cells correlated with enhanced α4β1‐mediated cell lodging in the BM, and with disease progression. BTZ‐resistant MM cells displayed enhanced NF‐κB pathway activation relative to parental counterparts, which contributed to upregulated α4 expression and to α4β1‐dependent MM cell adhesion. These data emphasize the upregulation of α4β1 expression and function as a key event during resistance to BTZ in MM, which might indirectly contribute to stabilize this resistance, as stronger MM cell attachment to BM stroma will regain CAM‐DR and MM cell growth and survival. Finally, we found a strong correlation between high ITGB1 (integrin β1) expression in MM and poor progression‐free survival (PFS) and overall survival (OS) during treatment of MM patients with BTZ and IMIDs, and combination of high ITGB1 levels and presence of the high‐risk genetic factor amp1q causes low PFS and OS. These results unravel a novel prognostic value for ITGB1 in myeloma. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.