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CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma
SIMPLE SUMMARY: Multiple myeloma (MM) is an incurable disease for which novel therapeutic approaches targeting the malignant cells and the associated bone disease are urgently needed. CK1α is a protein kinase that plays a crucial role in the signaling network that sustains plasma cell (PC) survival...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454895/ https://www.ncbi.nlm.nih.gov/pubmed/36077711 http://dx.doi.org/10.3390/cancers14174173 |
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author | Fregnani, Anna Saggin, Lara Gianesin, Ketty Quotti Tubi, Laura Carraro, Marco Barilà, Gregorio Scapinello, Greta Bonetto, Giorgia Pesavento, Maria Berno, Tamara Branca, Antonio Gurrieri, Carmela Zambello, Renato Semenzato, Gianpietro Trentin, Livio Manni, Sabrina Piazza, Francesco |
author_facet | Fregnani, Anna Saggin, Lara Gianesin, Ketty Quotti Tubi, Laura Carraro, Marco Barilà, Gregorio Scapinello, Greta Bonetto, Giorgia Pesavento, Maria Berno, Tamara Branca, Antonio Gurrieri, Carmela Zambello, Renato Semenzato, Gianpietro Trentin, Livio Manni, Sabrina Piazza, Francesco |
author_sort | Fregnani, Anna |
collection | PubMed |
description | SIMPLE SUMMARY: Multiple myeloma (MM) is an incurable disease for which novel therapeutic approaches targeting the malignant cells and the associated bone disease are urgently needed. CK1α is a protein kinase that plays a crucial role in the signaling network that sustains plasma cell (PC) survival and bone disease. This protein regulates Wnt/β-catenin signaling, which is fundamental for both MM cell survival and mesenchymal stromal cell (MSC) osteogenic differentiation. In this study, we investigated its involvement in MM–MSC cross-talk. We found that, by lowering CK1α expression levels in co-cultures of MM and MSC cells, expression of RUNX2—the master regulator of osteogenic differentiation—was regulated differently in the two cell types. Our data suggest the possibility of using a specific CK1α inhibitor as part of a novel therapeutic approach to selectively kill malignant PCs and overcome the blocking of osteogenic differentiation induced by MM cells in MSCs. ABSTRACT: Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and β-catenin signaling. CK1α is a negative regulator of the Wnt/β-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM–MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/β-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments. |
format | Online Article Text |
id | pubmed-9454895 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-94548952022-09-09 CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma Fregnani, Anna Saggin, Lara Gianesin, Ketty Quotti Tubi, Laura Carraro, Marco Barilà, Gregorio Scapinello, Greta Bonetto, Giorgia Pesavento, Maria Berno, Tamara Branca, Antonio Gurrieri, Carmela Zambello, Renato Semenzato, Gianpietro Trentin, Livio Manni, Sabrina Piazza, Francesco Cancers (Basel) Article SIMPLE SUMMARY: Multiple myeloma (MM) is an incurable disease for which novel therapeutic approaches targeting the malignant cells and the associated bone disease are urgently needed. CK1α is a protein kinase that plays a crucial role in the signaling network that sustains plasma cell (PC) survival and bone disease. This protein regulates Wnt/β-catenin signaling, which is fundamental for both MM cell survival and mesenchymal stromal cell (MSC) osteogenic differentiation. In this study, we investigated its involvement in MM–MSC cross-talk. We found that, by lowering CK1α expression levels in co-cultures of MM and MSC cells, expression of RUNX2—the master regulator of osteogenic differentiation—was regulated differently in the two cell types. Our data suggest the possibility of using a specific CK1α inhibitor as part of a novel therapeutic approach to selectively kill malignant PCs and overcome the blocking of osteogenic differentiation induced by MM cells in MSCs. ABSTRACT: Multiple myeloma (MM) is a malignant plasma cell (PC) neoplasm, which also displays pathological bone involvement. Clonal expansion of MM cells in the bone marrow causes a perturbation of bone homeostasis that culminates in MM-associated bone disease (MMABD). We previously demonstrated that the S/T kinase CK1α sustains MM cell survival through the activation of AKT and β-catenin signaling. CK1α is a negative regulator of the Wnt/β-catenin cascade, the activation of which promotes osteogenesis by directly stimulating the expression of RUNX2, the master gene regulator of osteoblastogenesis. In this study, we investigated the role of CK1α in the osteoblastogenic potential of mesenchymal stromal cells (MSCs) and its involvement in MM–MSC cross-talk. We found that CK1α silencing in in vitro co-cultures of MMs and MSCs modulated RUNX2 expression differently in PCs and in MSCs, mainly through the regulation of Wnt/β-catenin signaling. Our findings suggest that the CK1α/RUNX2 axis could be a potential therapeutic target for constraining malignant PC expansion and supporting the osteoblastic transcriptional program of MSCs, with potential for ameliorating MMABD. Moreover, considering that Lenalidomide treatment leads to MM cell death through Ikaros, Aiolos and CK1α proteasomal degradation, we examined its effects on the osteoblastogenic potential of MSC compartments. MDPI 2022-08-29 /pmc/articles/PMC9454895/ /pubmed/36077711 http://dx.doi.org/10.3390/cancers14174173 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Fregnani, Anna Saggin, Lara Gianesin, Ketty Quotti Tubi, Laura Carraro, Marco Barilà, Gregorio Scapinello, Greta Bonetto, Giorgia Pesavento, Maria Berno, Tamara Branca, Antonio Gurrieri, Carmela Zambello, Renato Semenzato, Gianpietro Trentin, Livio Manni, Sabrina Piazza, Francesco CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma |
title | CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma |
title_full | CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma |
title_fullStr | CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma |
title_full_unstemmed | CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma |
title_short | CK1α/RUNX2 Axis in the Bone Marrow Microenvironment: A Novel Therapeutic Target in Multiple Myeloma |
title_sort | ck1α/runx2 axis in the bone marrow microenvironment: a novel therapeutic target in multiple myeloma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9454895/ https://www.ncbi.nlm.nih.gov/pubmed/36077711 http://dx.doi.org/10.3390/cancers14174173 |
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