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ICAP‐1 regulates β1‐integrin activation and cell adhesion. Here, we used ICAP‐1‐null mice to study ICAP‐1 potential involvement during immune cell development and function. Integrin α4β1‐dependent adhesion was comparable between ICAP‐1‐null and control thymocytes, but lack of ICAP‐1 caused a defective single‐positive (SP) CD8+ cell generation, thus, unveiling an ICAP‐1 involvement in SP thymocyte development. ICAP‐1 bears a nuclear localization signal and we found it displayed a strong nuclear distribution in thymocytes. Interestingly, there was a direct correlation between the lack of ICAP‐1 and reduced levels in SP CD8+ thymocytes of Runx3, a transcription factor required for CD8+ thymocyte generation. In the spleen, ICAP‐1 was found evenly distributed between cytoplasm and nuclear fractions, and ICAP‐1–/– spleen T and B cells displayed upregulation of α4β1‐mediated adhesion, indicating that ICAP‐1 negatively controls their attachment. Furthermore, CD3+‐ and CD19+‐selected spleen cells from ICAP‐1‐null mice showed reduced proliferation in response to T‐ and B‐cell stimuli, respectively. Finally, loss of ICAP‐1 caused a remarkable decrease in marginal zone B‐ cell frequencies and a moderate increase in follicular B cells. Together, these data unravel an ICAP‐1 involvement in the generation of SP CD8+ thymocytes and in the control of marginal zone B‐cell numbers. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]