Myc可控表达的B细胞淋巴瘤小鼠模型的建立
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摘要
目的建立Myc可控表达的B细胞淋巴瘤小鼠模型。方法将p53敲除小鼠的骨髓细胞与编码Myc雌激素受体融合蛋白(MycER)病毒包装的细胞混合后注入小鼠皮下。腹腔注射他莫昔芬(TAM),1次/d。结果正常对照组小鼠未出现肿瘤;模型组小鼠持续注射TAM后,肿瘤迅速生长。停止注射TAM后,肿瘤大小迅速减小。3周后,肿瘤恢复生长,但速度较慢;此时若注射TAM,肿瘤生长异常加速。结论本研究通过TAM实现对Myc"失活"及"激活"两种状态的调控,成功建立Myc可控表达的B细胞淋巴瘤小鼠模型。
Objective To establish a Myc-inducible mouse model of B-cell lymphoma.Methods Mixture of fresh p53-null bone marrow cells and virus-packaging cells producing Myc estrogen receptor( MycER) retrovirus were injected into mice subcutaneously. Tamoxifen( TAM) was injected intra-peritoneally once a day. Results B lymphomas developed and were growing fast with injection of TAM,while there was no tumor development without injection of TAM. However,tumor growth was dramatically repressed after withdrawal of TAM. Interestingly,tumors grew slowly again three weeks later even without TAM injection,and abnormal acceleration of tumor growth occurred if TAM was re-administrated. Conclusion In this study,we successfully establish a B-cell lymphoma mouse model with controllable expression of Myc through TAM to regulate the inactivation and activation of Myc.
Objective To establish a Myc-inducible mouse model of B-cell lymphoma.Methods Mixture of fresh p53-null bone marrow cells and virus-packaging cells producing Myc estrogen receptor( MycER) retrovirus were injected into mice subcutaneously. Tamoxifen( TAM) was injected intra-peritoneally once a day. Results B lymphomas developed and were growing fast with injection of TAM,while there was no tumor development without injection of TAM. However,tumor growth was dramatically repressed after withdrawal of TAM. Interestingly,tumors grew slowly again three weeks later even without TAM injection,and abnormal acceleration of tumor growth occurred if TAM was re-administrated. Conclusion In this study,we successfully establish a B-cell lymphoma mouse model with controllable expression of Myc through TAM to regulate the inactivation and activation of Myc.
引文
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[5]郭晔.“双打击”B细胞淋巴瘤的研究进展[J].中国癌症杂志,2014,24(10):745-749.
[6]Buendia M A,Bourre L,Cairo S.Myc target miRs and liver cancer:small molecules to get Myc sick[J].Gastroenterology,2012,142(2):214-218.
[7]Malynn B A,de Alboran I M,O'Hagan R C,et al.N-Myc can functionally replace C-Myc in murine development,cellular growth,and differentiation[J].Genes Dev,2000,14(11):1390-1399.
[8]Harrington C T,Sotillo E,Robert A,et al.Transient stabilization,rather than inhibition,of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma[J].Leukemia,2019:Epub ahead of print.
[9]Bisso A,SabòA,Amati B.MYC in Germinal Center-derived lymphomas:Mechanisms and therapeutic opportunities[J].Immunol Rev,2019,288(1):178-197.
[10]Dang C V,O'Donnell K A,Zeller K I,et al.The C-Myc target gene network[J].Semin Cancer Biol,2006,16(4):253-264.
[11]Secombe J,Pierce S B,Eisenman R N.Myc:a weapon of mass destruction[J].Cell,2004,117(2):153-156.
[12]Dang C V.MYC on the path to cancer[J].Cell,2012,149(1):22-35.
[13]Vogelstein B,Lane D,Levine A J.Surfing the p53 network[J].Nature,2000,408(6810):307-310.
[14]el-Deiry W S.Regulation of p53 downstream genes[J].Semin Cancer Biol,1998,8(5):345-357.
[15]Harris S L,Levine A J.The p53 pathway:positive and negative feedback loops[J].Oncogene,2005,24(17):2899-2908.
[16]Vousden K H,Lu X.Live or let die:the cell's response to p53[J].Nat Rev Cancer,2002,2(8):594-604.
[17]Teodoro J G,Parker A E,Zhu X C,et al.p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase[J].Science,2006,313(5789):968-971.
[18]Yu D N,Dews M,Park A,et al.Inactivation of myc in murine two-hit b lymphomas causes dormancy with elevated levels of interleukin 10 receptor and CD20:implications for adjuvant therapies[J].Cancer Res,2005,65(12):5454-5461.
[19]Yu D N,Dews M,Park A,et al.Inactivation of Myc in murine two-hit B lymphomas causes dormancy with elevated levels of interleukin 10 receptor and CD20:implications for adjuvant therapies[J].Cancer Res,2005,65(12):5454-5461.
[20]Wolpaw A J,Dang C V.MYC-induced metabolic stress and tumorigenesis[J].Biochim Biophys Acta Rev Cancer,2018,1870(1):43-50.
[21]Patel J H,Loboda A P,Showe M K,et al.Analysis of genomic targets reveals complex functions of MYC[J].Nat Rev Cancer,2004,4(7):562-568.
[22]Hurley L H,Von Hoff D D,Siddiqui-Jain A,et al.Drug targeting of the C-Myc promoter to repress gene expression via a G-quadruplex silencer element[J].Semin Oncol,2006,33(4):498-512.
[2]Shah N N,Fry T J.Mechanisms of resistance to CAR T cell therapy[J].Nat Rev Clin Oncol,2019:Epub ahead of print.
[3]贺荣芳,谢黎明,赵强,等.B细胞淋巴瘤中E2F1、BIRC5、PLK1蛋白表达及其临床意义[J].临床与实验病理学杂志,2012,28(3):298-301.
[4]Dalla-Favera R,Lombardi L,Pelicci P G,et al.Mechanism of activation and biological role of the C-Myc oncogene in B-cell lymphomagenesis[J].Ann N Y Acad Sci,1987,511:207-218.
[5]郭晔.“双打击”B细胞淋巴瘤的研究进展[J].中国癌症杂志,2014,24(10):745-749.
[6]Buendia M A,Bourre L,Cairo S.Myc target miRs and liver cancer:small molecules to get Myc sick[J].Gastroenterology,2012,142(2):214-218.
[7]Malynn B A,de Alboran I M,O'Hagan R C,et al.N-Myc can functionally replace C-Myc in murine development,cellular growth,and differentiation[J].Genes Dev,2000,14(11):1390-1399.
[8]Harrington C T,Sotillo E,Robert A,et al.Transient stabilization,rather than inhibition,of MYC amplifies extrinsic apoptosis and therapeutic responses in refractory B-cell lymphoma[J].Leukemia,2019:Epub ahead of print.
[9]Bisso A,SabòA,Amati B.MYC in Germinal Center-derived lymphomas:Mechanisms and therapeutic opportunities[J].Immunol Rev,2019,288(1):178-197.
[10]Dang C V,O'Donnell K A,Zeller K I,et al.The C-Myc target gene network[J].Semin Cancer Biol,2006,16(4):253-264.
[11]Secombe J,Pierce S B,Eisenman R N.Myc:a weapon of mass destruction[J].Cell,2004,117(2):153-156.
[12]Dang C V.MYC on the path to cancer[J].Cell,2012,149(1):22-35.
[13]Vogelstein B,Lane D,Levine A J.Surfing the p53 network[J].Nature,2000,408(6810):307-310.
[14]el-Deiry W S.Regulation of p53 downstream genes[J].Semin Cancer Biol,1998,8(5):345-357.
[15]Harris S L,Levine A J.The p53 pathway:positive and negative feedback loops[J].Oncogene,2005,24(17):2899-2908.
[16]Vousden K H,Lu X.Live or let die:the cell's response to p53[J].Nat Rev Cancer,2002,2(8):594-604.
[17]Teodoro J G,Parker A E,Zhu X C,et al.p53-mediated inhibition of angiogenesis through up-regulation of a collagen prolyl hydroxylase[J].Science,2006,313(5789):968-971.
[18]Yu D N,Dews M,Park A,et al.Inactivation of myc in murine two-hit b lymphomas causes dormancy with elevated levels of interleukin 10 receptor and CD20:implications for adjuvant therapies[J].Cancer Res,2005,65(12):5454-5461.
[19]Yu D N,Dews M,Park A,et al.Inactivation of Myc in murine two-hit B lymphomas causes dormancy with elevated levels of interleukin 10 receptor and CD20:implications for adjuvant therapies[J].Cancer Res,2005,65(12):5454-5461.
[20]Wolpaw A J,Dang C V.MYC-induced metabolic stress and tumorigenesis[J].Biochim Biophys Acta Rev Cancer,2018,1870(1):43-50.
[21]Patel J H,Loboda A P,Showe M K,et al.Analysis of genomic targets reveals complex functions of MYC[J].Nat Rev Cancer,2004,4(7):562-568.
[22]Hurley L H,Von Hoff D D,Siddiqui-Jain A,et al.Drug targeting of the C-Myc promoter to repress gene expression via a G-quadruplex silencer element[J].Semin Oncol,2006,33(4):498-512.