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Title

Upregulated expression and function of the α4β1 integrin in multiple myeloma cells resistant to bortezomib

Other TitlesRunning head: Myeloma resistance to bortezomib and α4β1 expression and function
AuthorsSevilla-Movilla, Silvia; Arellano-Sánchez, Nohemí ; Martínez-Moreno, Mónica; Gajate, Consuelo ; Sánchez‐Vencells, Anna; Vitores Valcárcel, Luis; Agirre, X.; Valeri, Antonio; Martínez-López, Joaquín; Prosper, Felipe; Mollinedo, Faustino ; Teixidó, Joaquín
KeywordsMultiple myeloma
Integrins
Proteasome inhibitors
Resistance
Prognosis
Issue Date22-Jul-2020
PublisherJohn Wiley & Sons
CitationThe Journal of Pathology (2020)
AbstractThe 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 is 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.
Description36 p.-6 fig.
Publisher version (URL)https://doi.org/10.1002/path.5480
URIhttp://hdl.handle.net/10261/214009
DOIhttp://dx.doi.org/10.1002/path.5480
E-ISSN2056-4538
Appears in Collections:(CIB) Artículos
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