Increased function of a key adhesion receptor in multiple myeloma cells resistant to proteasome inhibitors

The group of Dr. Joaquin Teixidó at the Centro de Investigaciones Biológicas Margarita Salas has just published in J. Pathol.  A work which reports the enhancement of the expression and function of the integrin α4β1 in multiple myeloma (MM) cells resistant to the proteasome inhibitors bortezomib (BTZ) and carfilzomib. α4β1 is a critical adhesion receptor that upon interaction with its ligands fibronectin and VCAM-1 contributes to MM disease progression in the bone marrow (BM), thus indicating that upregulated α4β1 function during resistance to BTZ could worsen the relapse responses.

The interaction of MM cells with the BM microenvironment promotes MM cell retention, survival and resistance to different anti-MM agents, including proteasome inhibitors such as BTZ. α4β1 mediates 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 and MM cell apoptosis.

Silvia Sevilla-Movilla, Nohemi Arellano-Sánchez et al. have addressed whether decreased α4β1 expression and activity is maintained or recovered upon development of resistance to BTZ, which represents an important question, as a potential rescue of α4β1 function could boost MM cell survival and disease progression. Using BTZ-resistant MM cells, the authors found that they not only rescue their α4β1 expression, but its levels are 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. In addition, they 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 immunomodulatory drugs. Furthermore, they show that combination of high ITGB1 levels and presence of the high-risk genetic factor amp1q causes low PFS and OS. Therefore, these results unravel a novel prognostic value for ITGB1 in myeloma.

The work is the result of a collaboration with the groups of Dr. Faustino Mollinedo (CIB Margarita Salas), Joaquin Martínez-López (Hospital Universitario 12 de Octubre), and Xabier Agirre and Felipe Prósper (Centro de Investigación Médica Aplicada, Universidad de Navarra).

Reference: Upregulated expression and function of the α4β1 integrin in multiple myeloma cells resistant to bortezomib. Silvia Sevilla-Movilla, Nohemí Arellano-Sánchez, Mónica Martínez-Moreno, Consuelo Gajate, Anna Sánchez-Vencells, Luis Vitores Valcárcel, Xabier Agirre, Antonio Valeri, Joaquin Martínez-López, Felipe Prósper, Faustino Mollinedo and Joaquin Teixidó. (2020) J. Pathol. Jun 5. doi: 10.1002/path.5480. Online ahead of print.