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

dc.contributor.authorPetrusca, Daniela N.
dc.contributor.authorToscani, Denise
dc.contributor.authorWang, Feng-Ming
dc.contributor.authorPark, Cheolkyu
dc.contributor.authorCrean, Colin D.
dc.contributor.authorAnderson, Judith L.
dc.contributor.authorMarino, Silvia
dc.contributor.authorMohammad, Khalid S.
dc.contributor.authorZhou, Dan
dc.contributor.authorSilbermann, Rebecca
dc.contributor.authorSun, Quanhong
dc.contributor.authorKurihara, Noriyoshi
dc.contributor.authorGalson, Deborah L.
dc.contributor.authorGiuliani, Nicola
dc.contributor.authorRoodman, G. David
dc.contributor.departmentMedicine, School of Medicineen_US
dc.date.accessioned2019-05-17T17:33:33Z
dc.date.available2019-05-17T17:33:33Z
dc.date.issued2018-10-04
dc.description.abstractBACKGROUND: 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.en_US
dc.identifier.citationPetrusca, D. N., Toscani, D., Wang, F. M., Park, C., Crean, C. D., Anderson, J. L., … Roodman, G. D. (2018). Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis. Journal of hematology & oncology, 11(1), 123. doi:10.1186/s13045-018-0666-5en_US
dc.identifier.urihttps://hdl.handle.net/1805/19356
dc.language.isoen_USen_US
dc.publisherBiomed Centralen_US
dc.relation.isversionof10.1186/s13045-018-0666-5en_US
dc.relation.journalJournal of Hematology & Oncologyen_US
dc.rightsAttribution-NonCommercial-NoDerivs 3.0 United States*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/us/*
dc.sourcePMCen_US
dc.subjectApoptosisen_US
dc.subjectOsteolysisen_US
dc.subjectBone diseaseen_US
dc.subjectGfi1en_US
dc.subjectMultiple myelomaen_US
dc.titleGrowth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesisen_US
dc.typeArticleen_US
Files
Original bundle
Now showing 1 - 1 of 1
Loading...
Thumbnail Image
Name:
13045_2018_Article_666.pdf
Size:
5.3 MB
Format:
Adobe Portable Document Format
Description:
License bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
license.txt
Size:
1.99 KB
Format:
Item-specific license agreed upon to submission
Description: