| First Author | Sevilla-Movilla S | Year | 2020 |
| Journal | J Pathol | Volume | 252 |
| Issue | 1 | Pages | 29-40 |
| PubMed ID | 32501543 | Mgi Jnum | J:301408 |
| Mgi Id | MGI:6504286 | Doi | 10.1002/path.5480 |
| Citation | Sevilla-Movilla S, et al. (2020) Upregulated expression and function of the alpha4beta1 integrin in multiple myeloma cells resistant to bortezomib. J Pathol 252(1):29-40 |
| abstractText | 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 alpha4beta1 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 alpha4beta1 expression and activity are maintained or recovered upon development of resistance to BTZ represents an important question, as a potential rescue of alpha4beta1 function could boost MM cell survival and disease progression. Using BTZ-resistant MM cells, we found that they not only rescue their alpha4beta1 expression, but its levels were higher than in parental cells. Increased alpha4beta1 expression in resistant cells correlated with enhanced alpha4beta1-mediated cell lodging in the BM, and with disease progression. BTZ-resistant MM cells displayed enhanced NF-kappaB pathway activation relative to parental counterparts, which contributed to upregulated alpha4 expression and to alpha4beta1-dependent MM cell adhesion. These data emphasize the upregulation of alpha4beta1 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 beta1) 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. (c) 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. |
