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Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma
Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription fact...
Autores principales: | , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The American Society of Hematology
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405202/ https://www.ncbi.nlm.nih.gov/pubmed/36867577 http://dx.doi.org/10.1182/bloodadvances.2022009044 |
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author | Brownlie, Rebecca J. Kennedy, Ruth Wilson, Erica B. Milanovic, Maja Taylor, Claire F. Wang, Dapeng Davies, John R. Owston, Heather Adams, Emma J. Stephenson, Sophie Caeser, Rebecca Gewurz, Benjamin E. Giannoudis, Peter V. Scuoppo, Claudio McGonagle, Dennis Hodson, Daniel J. Tooze, Reuben M. Doody, Gina M. Cook, Gordon Westhead, David R. Klein, Ulf |
author_facet | Brownlie, Rebecca J. Kennedy, Ruth Wilson, Erica B. Milanovic, Maja Taylor, Claire F. Wang, Dapeng Davies, John R. Owston, Heather Adams, Emma J. Stephenson, Sophie Caeser, Rebecca Gewurz, Benjamin E. Giannoudis, Peter V. Scuoppo, Claudio McGonagle, Dennis Hodson, Daniel J. Tooze, Reuben M. Doody, Gina M. Cook, Gordon Westhead, David R. Klein, Ulf |
author_sort | Brownlie, Rebecca J. |
collection | PubMed |
description | Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules interleukin-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the messenger RNA and protein levels. IL-27Rα and JAM2 were expressed on primary MM cells at higher levels than on healthy long-lived plasma cells (PCs) in the bone marrow. IL-27 activated STAT1, and to a lesser extent STAT3, in MM cell lines and in PCs generated from memory B cells in an IL-21–dependent in vitro PC differentiation assay. Concomitant activity of IL-21 and IL-27 enhanced differentiation into PCs and increased the cell-surface expression of the known STAT target gene CD38. In accordance, a subset of MM cell lines and primary MM cells cultured with IL-27 upregulated CD38 cell-surface expression, a finding with potential implications for enhancing the efficacy of CD38-directed monoclonal antibody therapies by increasing CD38 expression on tumor cells. The elevated expression of IL-27Rα and JAM2 on MM cells compared with that on healthy PCs may be exploited for the development of targeted therapeutic strategies that modulate the interaction of MM cells with the TME. |
format | Online Article Text |
id | pubmed-10405202 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | The American Society of Hematology |
record_format | MEDLINE/PubMed |
spelling | pubmed-104052022023-08-08 Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma Brownlie, Rebecca J. Kennedy, Ruth Wilson, Erica B. Milanovic, Maja Taylor, Claire F. Wang, Dapeng Davies, John R. Owston, Heather Adams, Emma J. Stephenson, Sophie Caeser, Rebecca Gewurz, Benjamin E. Giannoudis, Peter V. Scuoppo, Claudio McGonagle, Dennis Hodson, Daniel J. Tooze, Reuben M. Doody, Gina M. Cook, Gordon Westhead, David R. Klein, Ulf Blood Adv Lymphoid Neoplasia Multiple myeloma (MM) shows constitutive activation of canonical and noncanonical nuclear factor κB (NF-κB) signaling via genetic mutations or tumor microenvironment (TME) stimulations. A subset of MM cell lines showed dependency for cell growth and survival on the canonical NF-κB transcription factor RELA alone, suggesting a critical role for a RELA-mediated biological program in MM pathogenesis. Here, we determined the RELA-dependent transcriptional program in MM cell lines and found the expression of the cell surface molecules interleukin-27 receptor-α (IL-27Rα) and the adhesion molecule JAM2 to be responsive to RELA at the messenger RNA and protein levels. IL-27Rα and JAM2 were expressed on primary MM cells at higher levels than on healthy long-lived plasma cells (PCs) in the bone marrow. IL-27 activated STAT1, and to a lesser extent STAT3, in MM cell lines and in PCs generated from memory B cells in an IL-21–dependent in vitro PC differentiation assay. Concomitant activity of IL-21 and IL-27 enhanced differentiation into PCs and increased the cell-surface expression of the known STAT target gene CD38. In accordance, a subset of MM cell lines and primary MM cells cultured with IL-27 upregulated CD38 cell-surface expression, a finding with potential implications for enhancing the efficacy of CD38-directed monoclonal antibody therapies by increasing CD38 expression on tumor cells. The elevated expression of IL-27Rα and JAM2 on MM cells compared with that on healthy PCs may be exploited for the development of targeted therapeutic strategies that modulate the interaction of MM cells with the TME. The American Society of Hematology 2023-03-08 /pmc/articles/PMC10405202/ /pubmed/36867577 http://dx.doi.org/10.1182/bloodadvances.2022009044 Text en © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Lymphoid Neoplasia Brownlie, Rebecca J. Kennedy, Ruth Wilson, Erica B. Milanovic, Maja Taylor, Claire F. Wang, Dapeng Davies, John R. Owston, Heather Adams, Emma J. Stephenson, Sophie Caeser, Rebecca Gewurz, Benjamin E. Giannoudis, Peter V. Scuoppo, Claudio McGonagle, Dennis Hodson, Daniel J. Tooze, Reuben M. Doody, Gina M. Cook, Gordon Westhead, David R. Klein, Ulf Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma |
title | Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma |
title_full | Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma |
title_fullStr | Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma |
title_full_unstemmed | Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma |
title_short | Cytokine receptor IL27RA is an NF-κB–responsive gene involved in CD38 upregulation in multiple myeloma |
title_sort | cytokine receptor il27ra is an nf-κb–responsive gene involved in cd38 upregulation in multiple myeloma |
topic | Lymphoid Neoplasia |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10405202/ https://www.ncbi.nlm.nih.gov/pubmed/36867577 http://dx.doi.org/10.1182/bloodadvances.2022009044 |
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