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The precise extent of NF-\u03baB activation and the contributions of the physical microenvironment and of cell-to-cell communications remain largely unknown. By quantitative immunofluorescence, we found that NF-\u03baB is mildly and heterogeneously activated in a fraction of MM cells in human BMs, while only a minority of MM cells shows a strong activation. To gain quantitative insights on NF-\u03baB activation in living MM cells, we combined advanced live imaging of endogenous p65 Venus-knocked-in in MM.1S and HS-5 cell lines to model MM and mesenchymal stromal cells (MSCs), cell co-cultures, microfluidics and custom microbioreactors to mimic the 3D-interactions within the bone marrow (BM) microenvironment. We found that i) reciprocal MM-MSC paracrine crosstalk and cell-to-scaffold interactions shape the inflammatory response in the BM; ii) the pro-inflammatory cytokine IL-1\u03b2, abundant in MM patients\u2019 plasma, activates MSCs, whose paracrine signals are responsible for strong NF-\u03baB activation in a minority of MM cells; iii) IL-1\u03b2, but not TNF-\u03b1, activates NF-\u03baB in vivo in BM-engrafted MM cells, while its receptor inhibitor Anakinra reduces the global NF-\u03baB activation. We propose that NF-\u03baB activation in the BM of MM patients is mild, restricted to a minority of cells and modulated by the interplay of restraining physical microenvironmental cues and activating IL-1\u03b2-dependent stroma-to-MM crosstalk.<\/jats:p>","DOI":"10.1038\/s41419-024-07038-1","type":"journal-article","created":{"date-parts":[[2024,10,6]],"date-time":"2024-10-06T07:01:28Z","timestamp":1728198088000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["In vitro models of the crosstalk between multiple myeloma and stromal cells recapitulate the mild NF-\u03baB activation observed in vivo"],"prefix":"10.1038","volume":"15","author":[{"given":"Federica","family":"Colombo","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Guzzeloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cise","family":"Kizilirmak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Brambilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5481-040X","authenticated-orcid":false,"given":"Jose Manuel","family":"Garcia-Manteiga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Sofia","family":"Tascini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Moalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Mercalli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maurilio","family":"Ponzoni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1271-8998","authenticated-orcid":false,"given":"Rosanna","family":"Mezzapelle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Ferrarini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Ferrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Visone","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2904-8652","authenticated-orcid":false,"given":"Marco","family":"Rasponi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5329-6445","authenticated-orcid":false,"given":"Marco E.","family":"Bianchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9384-2017","authenticated-orcid":false,"given":"Samuel","family":"Zambrano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5006-9506","authenticated-orcid":false,"given":"Alessandra","family":"Agresti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,10,6]]},"reference":[{"key":"7038_CR1","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1038\/nrclinonc.2017.197","volume":"15","author":"IM Ghobrial","year":"2018","unstructured":"Ghobrial IM, Detappe A, Anderson KC, Steensma DP. 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