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Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis

BACKGROUND: In spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug-resistant clones. We previously showed that MM cells upregulate the transcriptional repressor, growth factor independence 1 (Gfi1), in bone marrow stromal cell...

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Autores principales: Petrusca, Daniela N, Toscani, Denise, Wang, Feng-Ming, Park, Cheolkyu, Crean, Colin D, Anderson, Judith L, Marino, Silvia, Mohammad, Khalid S, Zhou, Dan, Silbermann, Rebecca, Sun, Quanhong, Kurihara, Noriyoshi, Galson, Deborah L, Giuliani, Nicola, Roodman, G David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172782/
https://www.ncbi.nlm.nih.gov/pubmed/30286780
http://dx.doi.org/10.1186/s13045-018-0666-5
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author Petrusca, Daniela N
Toscani, Denise
Wang, Feng-Ming
Park, Cheolkyu
Crean, Colin D
Anderson, Judith L
Marino, Silvia
Mohammad, Khalid S
Zhou, Dan
Silbermann, Rebecca
Sun, Quanhong
Kurihara, Noriyoshi
Galson, Deborah L
Giuliani, Nicola
Roodman, G David
author_facet Petrusca, Daniela N
Toscani, Denise
Wang, Feng-Ming
Park, Cheolkyu
Crean, Colin D
Anderson, Judith L
Marino, Silvia
Mohammad, Khalid S
Zhou, Dan
Silbermann, Rebecca
Sun, Quanhong
Kurihara, Noriyoshi
Galson, Deborah L
Giuliani, Nicola
Roodman, G David
author_sort Petrusca, Daniela N
collection PubMed
description BACKGROUND: In spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug-resistant clones. We previously showed that MM cells upregulate the transcriptional repressor, growth factor independence 1 (Gfi1), in bone marrow stromal cells (BMSCs) that induces prolonged inhibition of osteoblast differentiation. However, the role of Gfi1 in MM cells is unknown. METHODS: Human primary CD138+ and BMSC were purified from normal donors and MM patients’ bone marrow aspirates. Gfi1 knockdown and overexpressing cells were generated by lentiviral-mediated shRNA. Proliferation/apoptosis studies were done by flow cytometry, and protein levels were determined by Western blot and/or immunohistochemistry. An experimental MM mouse model was generated to investigate the effects of MM cells overexpressing Gfi1 on tumor burden and osteolysis in vivo. RESULTS: We found that Gfi1 expression is increased in patient’s MM cells and MM cell lines and was further increased by co-culture with BMSC, IL-6, and sphingosine-1-phosphate. Modulation of Gfi1 in MM cells had major effects on their survival and growth. Knockdown of Gfi1 induced apoptosis in p53-wt, p53-mutant, and p53-deficient MM cells, while Gfi1 overexpression enhanced MM cell growth and protected MM cells from bortezomib-induced cell death. Gfi1 enhanced cell survival of p53-wt MM cells by binding to p53, thereby blocking binding to the promoters of the pro-apoptotic BAX and NOXA genes. Further, Gfi1-p53 binding could be blocked by HDAC inhibitors. Importantly, inoculation of MM cells overexpressing Gfi1 in mice induced increased bone destruction, increased osteoclast number and size, and enhanced tumor growth. CONCLUSIONS: These results support that Gfi1 plays a key role in MM tumor growth, survival, and bone destruction and contributes to bortezomib resistance, suggesting that Gfi1 may be a novel therapeutic target for MM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-018-0666-5) contains supplementary material, which is available to authorized users.
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spelling pubmed-61727822018-10-15 Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis Petrusca, Daniela N Toscani, Denise Wang, Feng-Ming Park, Cheolkyu Crean, Colin D Anderson, Judith L Marino, Silvia Mohammad, Khalid S Zhou, Dan Silbermann, Rebecca Sun, Quanhong Kurihara, Noriyoshi Galson, Deborah L Giuliani, Nicola Roodman, G David J Hematol Oncol Research BACKGROUND: In spite of major advances in treatment, multiple myeloma (MM) is currently an incurable malignancy due to the emergence of drug-resistant clones. We previously showed that MM cells upregulate the transcriptional repressor, growth factor independence 1 (Gfi1), in bone marrow stromal cells (BMSCs) that induces prolonged inhibition of osteoblast differentiation. However, the role of Gfi1 in MM cells is unknown. METHODS: Human primary CD138+ and BMSC were purified from normal donors and MM patients’ bone marrow aspirates. Gfi1 knockdown and overexpressing cells were generated by lentiviral-mediated shRNA. Proliferation/apoptosis studies were done by flow cytometry, and protein levels were determined by Western blot and/or immunohistochemistry. An experimental MM mouse model was generated to investigate the effects of MM cells overexpressing Gfi1 on tumor burden and osteolysis in vivo. RESULTS: We found that Gfi1 expression is increased in patient’s MM cells and MM cell lines and was further increased by co-culture with BMSC, IL-6, and sphingosine-1-phosphate. Modulation of Gfi1 in MM cells had major effects on their survival and growth. Knockdown of Gfi1 induced apoptosis in p53-wt, p53-mutant, and p53-deficient MM cells, while Gfi1 overexpression enhanced MM cell growth and protected MM cells from bortezomib-induced cell death. Gfi1 enhanced cell survival of p53-wt MM cells by binding to p53, thereby blocking binding to the promoters of the pro-apoptotic BAX and NOXA genes. Further, Gfi1-p53 binding could be blocked by HDAC inhibitors. Importantly, inoculation of MM cells overexpressing Gfi1 in mice induced increased bone destruction, increased osteoclast number and size, and enhanced tumor growth. CONCLUSIONS: These results support that Gfi1 plays a key role in MM tumor growth, survival, and bone destruction and contributes to bortezomib resistance, suggesting that Gfi1 may be a novel therapeutic target for MM. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13045-018-0666-5) contains supplementary material, which is available to authorized users. BioMed Central 2018-10-04 /pmc/articles/PMC6172782/ /pubmed/30286780 http://dx.doi.org/10.1186/s13045-018-0666-5 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Petrusca, Daniela N
Toscani, Denise
Wang, Feng-Ming
Park, Cheolkyu
Crean, Colin D
Anderson, Judith L
Marino, Silvia
Mohammad, Khalid S
Zhou, Dan
Silbermann, Rebecca
Sun, Quanhong
Kurihara, Noriyoshi
Galson, Deborah L
Giuliani, Nicola
Roodman, G David
Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
title Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
title_full Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
title_fullStr Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
title_full_unstemmed Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
title_short Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
title_sort growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172782/
https://www.ncbi.nlm.nih.gov/pubmed/30286780
http://dx.doi.org/10.1186/s13045-018-0666-5
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