A novel mouse model of adult T-cell leukemia cell invasion into the spinal cord
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摘要
Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-Prkdc~ (scid) Il2 rg ~(tm1Wjl)/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly(I.M.) at 5 weeks of age, 8(80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously(S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.
Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-Prkdc~ (scid) Il2 rg ~(tm1Wjl)/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly(I.M.) at 5 weeks of age, 8(80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously(S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.
Adult T-cell leukemia( ATL) is a mature T-cell malignancy caused by human T-cell leukemia virus type I infection, and 10%-25% of patients show central nervous system( CNS) involvement. CNS involvement significantly reduces survival and there are no effective treatments for CNS involvement. Therefore, an appropriate animal model is required to evaluate the inhibitory effects of novel drugs on the progression of ATL with CNS involvement. Here, we established a mouse model of ATL with CNS involvement using NOD.Cg-Prkdc~ (scid) Il2 rg ~(tm1Wjl)/SzJ mice inoculated with ATL cells intramuscularly in the postauricular region, and these mice showed paraparesis. Of the 10 mice inoculated with ATL cells intramuscularly(I.M.) at 5 weeks of age, 8(80%) showed paraparesis, whereas none of the 10 mice inoculated with ATL cells subcutaneously(S.C.) showed paraparesis. In the I.M. group, PCR detected HTLV-1-specific genes in the thoracic and lumbar vertebrae; however, in the S.C. group, the vertebrae were negative for HTLV-1 genes. Histological analysis revealed a particularly high incidence of tumors, characterized by accumulation of the injected cells, in the thoracic vertebrae of mice in the I.M. group. Tumor cell infiltration was relatively high in the bone marrow. Spinal cord compression caused by invasion of the tumor mass outside the pia mater was observed in the thoracic vertebrae of the spinal cord. In conclusion, we have reported a mouse model of tumor growth with paraparesis that may be used to assess novel therapeutic agents for ATL with CNS involvement.
引文
1.Uchiyama T.Human T cell leukemia virus type I(HTLV-I)and human diseases.Annu Rev Immunol.1997;15:15-37.
2.Watanabe T.HTLV-1-associated diseases.Int J Hematol.1997;66:257-278.
3.Utsunomiya A,Choi I,Chihara D,Seto M.Recent advances in the treatment of adult T-cell leukemia-lymphomas.Cancer Sci.2015;106:344-351.
4.Kawasaki C,Ikeda H,Fukumoto T.Cerebral mass lesions associated with adult T-cell leukemia/lymphoma.Int J Hematol.1995;61:97-102.
5.Teshima T,Akashi K,Shibuya T,et al.Central nervous system involvement in adult T-cell leukemia/lymphoma.Cancer.1990;65:327-332.
6.Niewiesk S.Animals Models of human T cell leukemia virus type Ileukemogenesis.ILAR J.2016;57:3-11.
7.Arima N,Arimura K,Tokito Y,et al.HTLV-I Tax protein inhibits apoptosis induction but not G1 arrest by pyrrolidinedithiocarbamate,an antioxidant,in adult T cell leukemia cells.Exp Hematol.2004;32:195-201.
8.Ohsugi T,Kumasaka T,Okada S,et al.Dehydroxymethylepoxyquinomicin(DHMEQ)therapy reduces tumor formation in mice inoculated with tax-deficient adult T-cell leukemia-derived cell lines.Cancer Lett.2007;257:206-215.
9.Ohsugi T,Koito A.Current topics in prevention of human T-cell leukemia virus type i infection:NF-kappa B inhibitors and APOBEC3.Int Rev Immunol.2008;27:225-253.
10.Turner PV,Brabb T,Pekow C,Vasbinder MA.Administration of substances to laboratory animals:routes of administration and factors to consider.J Am Assoc Lab Anim Sci.2011;50:600-613.
11.Ishihara S,Tachibana N,Okayama A,Murai K,Tsuda K,Mueller N.Successful graft of HTLV-I-transformed human T-cells(MT-2)in severe combined immunodeficiency mice treated with anti-asialo GM-1 antibody.Jpn J Cancer Res.1992;83:320-323.
2.Watanabe T.HTLV-1-associated diseases.Int J Hematol.1997;66:257-278.
3.Utsunomiya A,Choi I,Chihara D,Seto M.Recent advances in the treatment of adult T-cell leukemia-lymphomas.Cancer Sci.2015;106:344-351.
4.Kawasaki C,Ikeda H,Fukumoto T.Cerebral mass lesions associated with adult T-cell leukemia/lymphoma.Int J Hematol.1995;61:97-102.
5.Teshima T,Akashi K,Shibuya T,et al.Central nervous system involvement in adult T-cell leukemia/lymphoma.Cancer.1990;65:327-332.
6.Niewiesk S.Animals Models of human T cell leukemia virus type Ileukemogenesis.ILAR J.2016;57:3-11.
7.Arima N,Arimura K,Tokito Y,et al.HTLV-I Tax protein inhibits apoptosis induction but not G1 arrest by pyrrolidinedithiocarbamate,an antioxidant,in adult T cell leukemia cells.Exp Hematol.2004;32:195-201.
8.Ohsugi T,Kumasaka T,Okada S,et al.Dehydroxymethylepoxyquinomicin(DHMEQ)therapy reduces tumor formation in mice inoculated with tax-deficient adult T-cell leukemia-derived cell lines.Cancer Lett.2007;257:206-215.
9.Ohsugi T,Koito A.Current topics in prevention of human T-cell leukemia virus type i infection:NF-kappa B inhibitors and APOBEC3.Int Rev Immunol.2008;27:225-253.
10.Turner PV,Brabb T,Pekow C,Vasbinder MA.Administration of substances to laboratory animals:routes of administration and factors to consider.J Am Assoc Lab Anim Sci.2011;50:600-613.
11.Ishihara S,Tachibana N,Okayama A,Murai K,Tsuda K,Mueller N.Successful graft of HTLV-I-transformed human T-cells(MT-2)in severe combined immunodeficiency mice treated with anti-asialo GM-1 antibody.Jpn J Cancer Res.1992;83:320-323.