Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis.
Growth factor independence 1 expression in myeloma cells enhances their growth, survival, and osteoclastogenesis.
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DOI：
10.1186/s13045-018-0666-5
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发表时间：
2018-10-04
影响因子：
28.5
通讯作者：
Roodman GD
中科院分区：
文献类型：
--
作者：
Petrusca DN;Toscani D;Wang FM;Park C;Crean CD;Anderson JL;Marino S;Mohammad KS;Zhou D;Silbermann R;Sun Q;Kurihara N;Galson DL;Giuliani N;Roodman GD
尽管在治疗方面取得了重大进展，但由于出现了耐药克隆，多发性骨髓瘤（MM）目前仍是一种无法治愈的恶性肿瘤。我们以前的研究表明，MM细胞上调了骨髓基质细胞（BMSCs）中的转录抑制因子生长因子非依赖性1（Gfi 1），从而诱导成骨细胞分化的长期抑制。然而，Gfi 1在MM细胞中的作用尚不清楚。从正常供体和MM患者的骨髓抽吸物中纯化人原代CD 138+和BMSC。通过慢病毒介导的shRNA产生Gfi 1敲低和过表达细胞。通过流式细胞术进行增殖/凋亡研究，并通过Western印迹和/或免疫组织化学测定蛋白水平。生成实验性MM小鼠模型以研究过表达Gfi 1的MM细胞对体内肿瘤负荷和骨质溶解的影响。我们发现Gfi 1在患者的MM细胞和MM细胞系中的表达增加，并且通过与BMSC、IL-6和鞘氨醇-1-磷酸共培养进一步增加。MM细胞中Gfi 1的调节对其存活和生长有重要影响。在p53-wt、p53-突变体和p53-缺陷型MM细胞中，Gfi 1的敲低诱导凋亡，而Gfi 1的过表达增强MM细胞生长并保护MM细胞免于硼替佐米诱导的细胞死亡。Gfi 1通过与p53结合，从而阻断与促凋亡BAX和NOXA基因启动子的结合，增强了p53-wt MM细胞的细胞存活。此外，Gfil-p53结合可被HDAC抑制剂阻断。重要的是，在小鼠中接种过表达Gfi 1的MM细胞诱导骨破坏增加，破骨细胞数量和大小增加，并增强肿瘤生长。这些结果支持Gfi 1在MM肿瘤生长、存活和骨破坏中起关键作用，并有助于硼替佐米耐药性，表明Gfi 1可能是MM的新治疗靶点。本文的在线版本（10.1186/s13045-018-0666-5）包含补充材料，可供授权用户使用。
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. 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. 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. 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. 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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影响因子：
11.4
作者：
Kumar SK;Lee JH;Lahuerta JJ;Morgan G;Richardson PG;Crowley J;Haessler J;Feather J;Hoering A;Moreau P;LeLeu X;Hulin C;Klein SK;Sonneveld P;Siegel D;Bladé J;Goldschmidt H;Jagannath S;Miguel JS;Orlowski R;Palumbo A;Sezer O;Rajkumar SV;Durie BG;International Myeloma Working Group
通讯作者：
International Myeloma Working Group
影响因子：
11.4
作者：
Chng, W-J;Huang, G. F.;Chung, T. H.;Ng, S. B.;Gonzalez-Paz, N.;Troska-Price, T.;Mulligan, G.;Chesi, M.;Bergsagel, P. L.;Fonseca, R.
通讯作者：
Fonseca, R.
影响因子：
50.3
作者：
Khandanpour C;Phelan JD;Vassen L;Schütte J;Chen R;Horman SR;Gaudreau MC;Krongold J;Zhu J;Paul WE;Dührsen U;Göttgens B;Grimes HL;Möröy T
通讯作者：
Möröy T
影响因子：
23.9
作者：
Liu Y;Elf SE;Miyata Y;Sashida G;Liu Y;Huang G;Di Giandomenico S;Lee JM;Deblasio A;Menendez S;Antipin J;Reva B;Koff A;Nimer SD
通讯作者：
Nimer SD
影响因子：
3.7
作者：
Boyd, Kevin D.;Ross, Fiona M.;Morgan, Gareth J.
通讯作者：
Morgan, Gareth J.