STI571联用As_2O_3对K562细胞增殖和凋亡及Bcr-Abl、JAK-STAT蛋白表达的影响
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摘要
目的 研究STI571和As_2O_3单用及联用对K562细胞增殖和凋亡的影响,并观察STI571、As_2O_3单用及联用对K562细胞Bcr-Abl蛋白及其下游信号分子JAK2、STAT5酪氨酸磷酸化的影响,探讨其抗白血病的分子机制,为STI571和As_2O_3在临床上联合应用治疗CML提供理论依据。
方法 细胞增殖采用细胞生长及活力测定;细胞凋亡采用细胞形态、Annexin-V/PI双染实验、DNA的PI染色及DNA电泳等方法测定;运用免疫沉淀、Western blot实验分析K562细胞Bcr-Abl蛋白及其下游信号分子JAK2、STAT5酪氨酸磷酸化水平。
结果 在STI571和(或)As_2O_3作用下K562细胞生长明显受抑并伴随活力下降;细胞形态学观察到了典型的凋亡形态改变;流式细胞仪检测出凋亡细胞百分率呈时间剂量依赖关系;细胞周期检测示G_1期和S期细胞明显减少,细胞阻滞在G_2/M期;基因组DNA电泳出现“梯”状条带;Western blot结果显示K562细胞在STI571、As_2O_3作用下其Bcr-Abl蛋白及下游信号分子JAK2、STAT5酪氨酸磷酸化表达水平下调。
结论 STI571和As_2O_3均有抑制K562细胞增殖和诱导细胞凋亡的作用,两药联用效果更明显;K562细胞增殖抑制的机制可能与两药能诱导其细胞凋亡有关;STI571和As_2O_3诱导K562细胞凋亡的机制可能
Objective To investigate the effects of STI571 alone and in combination with AS_2O_3 on proliferation and apoptosis of the K562 cells; To observe the effects of STI571 alone and in combination with AS_2O_3 on Bcr-Abl, JAK2 and STAT5 protein tyrosine phosphorylation in K562 cells and to explore their molecular mechanism of antileukemia, to provide theoretical basis of the combination of the two drugs for clinical therapy of CML cases.Methods Cell proliferation was analyzed by the growth of cell and the viability of cell; Apoptosis was analyzed by cell morphology, Annexin-V/PI staining, DNA-PI staining, and DNA gel electrophoresis; Bcr-Abl, JAK2 and STAT5 protein tyrosine phosphorylation was studied by means of immunoprecipition and Western blot.Results After exposure to STI571 and/or As_2O_3, the growth of K562 cells was obviously inhibited and the viability of K562 cells was decreased; Typical apoptotic cell morphology was find by the Wright's staining method; The percentage of apoptotic cells was a time- and dose- dependent manner. STI571 and AS_2O_3 both could make K562 cells arrest in G_2/M phase, and the number of cells in G_1 phase and S phase decreases significantly; Typical DNA ladder was shown by DNA gel electrophoresis. Tyrosine phosphorylation levels
of Bcr-Abl, JAK2 and STAT5 were decreased in a time- and dose- dependent manner.Conclusion STI571 and As2O3 both could induce apoptosis of the K562 cells and inhibit its proliferation, the combination of the two drugs is better with the result. The mechanism of STI571 and AS2O3 inhibit proliferation of the K562 cells might be in connection with induce its apoptosis. The mechanism of STI571 and AS2O3 induce apoptosis of the K562 cells might be related to down-regulated expressions of Bcr-Abl in K562 cells, to interfere with the JAK-STAT signal transduction.
方法 细胞增殖采用细胞生长及活力测定;细胞凋亡采用细胞形态、Annexin-V/PI双染实验、DNA的PI染色及DNA电泳等方法测定;运用免疫沉淀、Western blot实验分析K562细胞Bcr-Abl蛋白及其下游信号分子JAK2、STAT5酪氨酸磷酸化水平。
结果 在STI571和(或)As_2O_3作用下K562细胞生长明显受抑并伴随活力下降;细胞形态学观察到了典型的凋亡形态改变;流式细胞仪检测出凋亡细胞百分率呈时间剂量依赖关系;细胞周期检测示G_1期和S期细胞明显减少,细胞阻滞在G_2/M期;基因组DNA电泳出现“梯”状条带;Western blot结果显示K562细胞在STI571、As_2O_3作用下其Bcr-Abl蛋白及下游信号分子JAK2、STAT5酪氨酸磷酸化表达水平下调。
结论 STI571和As_2O_3均有抑制K562细胞增殖和诱导细胞凋亡的作用,两药联用效果更明显;K562细胞增殖抑制的机制可能与两药能诱导其细胞凋亡有关;STI571和As_2O_3诱导K562细胞凋亡的机制可能
Objective To investigate the effects of STI571 alone and in combination with AS_2O_3 on proliferation and apoptosis of the K562 cells; To observe the effects of STI571 alone and in combination with AS_2O_3 on Bcr-Abl, JAK2 and STAT5 protein tyrosine phosphorylation in K562 cells and to explore their molecular mechanism of antileukemia, to provide theoretical basis of the combination of the two drugs for clinical therapy of CML cases.Methods Cell proliferation was analyzed by the growth of cell and the viability of cell; Apoptosis was analyzed by cell morphology, Annexin-V/PI staining, DNA-PI staining, and DNA gel electrophoresis; Bcr-Abl, JAK2 and STAT5 protein tyrosine phosphorylation was studied by means of immunoprecipition and Western blot.Results After exposure to STI571 and/or As_2O_3, the growth of K562 cells was obviously inhibited and the viability of K562 cells was decreased; Typical apoptotic cell morphology was find by the Wright's staining method; The percentage of apoptotic cells was a time- and dose- dependent manner. STI571 and AS_2O_3 both could make K562 cells arrest in G_2/M phase, and the number of cells in G_1 phase and S phase decreases significantly; Typical DNA ladder was shown by DNA gel electrophoresis. Tyrosine phosphorylation levels
of Bcr-Abl, JAK2 and STAT5 were decreased in a time- and dose- dependent manner.Conclusion STI571 and As2O3 both could induce apoptosis of the K562 cells and inhibit its proliferation, the combination of the two drugs is better with the result. The mechanism of STI571 and AS2O3 inhibit proliferation of the K562 cells might be in connection with induce its apoptosis. The mechanism of STI571 and AS2O3 induce apoptosis of the K562 cells might be related to down-regulated expressions of Bcr-Abl in K562 cells, to interfere with the JAK-STAT signal transduction.
引文
1. Nowell PC, Hungerford DA. A minute chromosome in human chronic granulocytic leukemia. Science, 1996, 132:1497-1497.
2. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature, 1973,243: 290-293.
3. Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell, 1984, 36(1): 93-99.
4. Kurzrock R, Gutterman JU, Talpaz M. The molecular geneties of Philadelphia chromosome positive leukemia. N Engl J Med, 1988, 319(15): 990-998.
5. O'Dwyer ME, Mauro M J, Druker BJ. Recent advancements in the treatment of chronic myelogenous leukemia. Annu Rev Med, 2002, 53: 369-381.
6. Druker B J, Talpaz M, Resta D J, et al. Efficacy and safety of.a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med, 2001, 344: 1031-1037.
7.孙鸿德,马玲,胡晓晨,等.癌灵一号结合中医辨证治疗急性早幼粒白血病32例.中国中西医结合杂志,1972,12:170-171.
8. Jiang XH, Wong BC, Yuen ST, et al. Arsenic trioxide induces apoptosis in human gastric cancer cells through up-regulation of p53 and activation of caspase-3. Int J Cancer, 2001, 91:173-179.
9. Mahieux R, Pise-Masison C, Gessain A, et al. Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1-and type 2-infected cells by a caspase-3-dependent mechanism involving Bcl-2 cleavage. Blood, 2001, 98: 3762-3769.
10.蔡循,贾培敏,石学耕,等.氧化砷诱导维甲酸耐药早幼粒细胞白血病细胞MR-2凋亡的体外研究.中华血液学杂志,1998,19:339-341.
11.肖冬梅,孙关林,邬维礼,等.As_2O_3诱导K562细胞凋亡过程中酪氨酸蛋白激酶活性的变化.中华血液学杂志,1998,19:234-237.
12.肖冬梅,孙关林,苏卉,等.As_2O_3对K562细胞BCR-ABL蛋白酪氨酸磷酸化的影响.中华血液学杂志,1999,20:637-639.
13.张日,朱子玲,仇红霞,等.三氧化二砷诱导K562细胞凋亡的初步研究.苏州医学院学报,1999,19:1156-1158.
14.张日,支雅军,陶瑞芳,等.亚砷酸钠治疗加速期慢性粒细胞性白血病的疗效观察.临床肿瘤学杂志,2000,5:263-265.
15.张日,支雅军,朱子玲,等.三氧化二砷联合木黄酮抑制CML细胞增殖的研究.江苏医药,2000,26:763-765.
16. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med, 1999, 341(3): 164-172.
17. Deininger MWN, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood, 2000, 96: 3343-3356.
18. O'Dwyer ME, Mauro M J, Druker BJ. Recent advancements in the treatment of chronic myelogenous leukemia. Annu Rev Med, 2002, 53:369-381.
19. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science, 2001,293: 876-880.
20. Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood, 2000, 96: 1070-1079.
21. O'Dwyer ME, Mauro MJ, Kuyl J, et al. Preliminary evaluation of the combination of imatinib mesylate(Gleevec) in combination with low dose interferon-alpha for the treatment of chronic phase CML. Blood, 2001 (suppl 1, abstr ), 98: 846a.
22. Rosti G, Trabacchi E, Bassi S, et al. Risk and early cytogenetic response to imatinib and interferon in chronic myeloid leukemia. Haematologica, 2003, 88: 256-259.
23. Guilhot F, Gardembas M, Rousselot P, et al. Imatinib in combination with cytarabine for the treatment of Philadelphia-postive chronic myelogenous leukemia chronic-phase patients : rational and design of phase Ⅰ/Ⅱ trials. Semin Hematol, 2003, 40: 92-97.
24. Thiesing JT, Ohno-Jones S, Kolibaba KS, et al. Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. Blood, 2000, 96:3195-3199.
25. Perkins C, Kim CN, Fang G, et al. Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress, MDR, MRP, Bc1-2, or Bcl-x(L). Blood, 2000, 95: 1014-1022.
26. McGabon A, Bissonette R, Schmitt M, et al. bcr-abl maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood, 1994, 83:1179-1187.
27. Cortez D, Stoica G,Pierce JH, et al. The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway. Oncogene, 1996, 13: 2589-2594.
28. Amarante-mendes GP, Kim C, Liu L, et al. Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome c and activation of caspase-3. Blood, 1998, 91:1700-1705.
29. La Rosee P, Johnson K, O'Dwyer ME, et al. In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol, 2002, 30: 729-737.
30. Zhang X, Subrahmanyam R, Wong R, et al. The NH2-terminal coiled-coil domain and tyrosine 177 Play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Mol Cell Biol, 2001, 21(3): 840-853.
31. Zhang X, Wong R, Hao SX, et al. The SH2 domain of Bcr-Abl is not required to induce a murine myeloproliferative disease; however, SH2 signaling influences disease latency and phenotype. Blood, 2001, 97(1): 277-287.
32. Deininger MW, Vieira S, Mendiola R, et al. BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res, 2000, 60(7): 2049-2055.
33. Porosnicu M, Nimmanapalli R, Nguyen D, et al. Co-treatment with As_2O_3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells. Leukemia, 2001, 15: 772-778.
34. Damell JE, Kerr LM, Stark GR. Jak-STAT pathway and transcriptional activation in response to IFNs and other extracellular signaling protein. Science, 1994, 264: 1415-1421.
35. Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet, 1995, 11 : 69-74.
36. Ihle JN. Signaling by the cytokine receptor superfamily in normal and transformed hematopoietic cells. Adv Cancer Res, 1996, 68: 23-65.
37. Ihle JN, Nosaka T, Thierfelder W, et al. Jaks and Stats in cytokine signaling. Stem Cells, 1997, 15(Suppl 1): 105-111.
38. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene, 2000, 19(21): 2628-2637.
39. Bromberg J, Damell JE Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene, 2000, 19(21): 2468-2473.
40. Levy DE, Lee CK. What does Stat3 do?. J Clin Invest, 2002, 109(9): 1143-1148.
41.扶云碧,张广森.BCR/ABL癌基因启动JAK/STAT信号转导途径的机制后果及意义.国外医学输血及血液学分册,2001,24(6):473-476.
42. Wilson-Rawls J, Liu J, Laneuville P. P210 Bcr-Abl interacts with the interleukin-3 beta c subunit and constitutively activates Jak2. Leukemia, 1997, 11(Suppl 3): 428-431.
43. Xie S, Wang Y, Liu JX, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene 2001, 20: 6188-6195.
44. Klejman A, Schreiner S J, Nieborowska-Skorska M, et al. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J, 2002, 21(21): 5766-5774.
45. Shuai K, Halpern J, ten Hoeve J, et al. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene, 1996, 13(2): 247-54.
46. Ilaria RL Jr, Van Etten RA. P210 and P 190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J. Biol. Chem, 1996, 271(49): 31704-31710.
47. de Groot RP, Raaij makers JA, Lammers JW, et al. STAT5 activation by BCR-ABL contributes to transformation of K562 leukemia cells. Blood, 1999, 94(3): 1108-1112.
48. Sillaber C, Gesbert F, Frank DA, et al. STAT5 activation contributes to growth and viability in Bcr/Abl transformed cells. Blood, 2000, 95(6): 2118-2125.
49. Horita M, Andreu EJ, Benito A, et al. Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-X_L. J Exp Med, 2000, 191(6): 977-984.
50. Jiang X, Lopez A, Holyoake T, et al. Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci USA, 1999, 96(22): 12804-12809.
51. Deininger MW, Vieira S, Mendiola R, et al . BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res, 2000, 60(7): 2049-2055.
2. Rowley JD. A new consistent chromosomal abnormality in chronic myelogenous leukemia identified by quinacrine fluorescence and Giemsa staining. Nature, 1973,243: 290-293.
3. Groffen J, Stephenson JR, Heisterkamp N, et al. Philadelphia chromosomal breakpoints are clustered within a limited region, bcr, on chromosome 22. Cell, 1984, 36(1): 93-99.
4. Kurzrock R, Gutterman JU, Talpaz M. The molecular geneties of Philadelphia chromosome positive leukemia. N Engl J Med, 1988, 319(15): 990-998.
5. O'Dwyer ME, Mauro M J, Druker BJ. Recent advancements in the treatment of chronic myelogenous leukemia. Annu Rev Med, 2002, 53: 369-381.
6. Druker B J, Talpaz M, Resta D J, et al. Efficacy and safety of.a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia. N Engl J Med, 2001, 344: 1031-1037.
7.孙鸿德,马玲,胡晓晨,等.癌灵一号结合中医辨证治疗急性早幼粒白血病32例.中国中西医结合杂志,1972,12:170-171.
8. Jiang XH, Wong BC, Yuen ST, et al. Arsenic trioxide induces apoptosis in human gastric cancer cells through up-regulation of p53 and activation of caspase-3. Int J Cancer, 2001, 91:173-179.
9. Mahieux R, Pise-Masison C, Gessain A, et al. Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1-and type 2-infected cells by a caspase-3-dependent mechanism involving Bcl-2 cleavage. Blood, 2001, 98: 3762-3769.
10.蔡循,贾培敏,石学耕,等.氧化砷诱导维甲酸耐药早幼粒细胞白血病细胞MR-2凋亡的体外研究.中华血液学杂志,1998,19:339-341.
11.肖冬梅,孙关林,邬维礼,等.As_2O_3诱导K562细胞凋亡过程中酪氨酸蛋白激酶活性的变化.中华血液学杂志,1998,19:234-237.
12.肖冬梅,孙关林,苏卉,等.As_2O_3对K562细胞BCR-ABL蛋白酪氨酸磷酸化的影响.中华血液学杂志,1999,20:637-639.
13.张日,朱子玲,仇红霞,等.三氧化二砷诱导K562细胞凋亡的初步研究.苏州医学院学报,1999,19:1156-1158.
14.张日,支雅军,陶瑞芳,等.亚砷酸钠治疗加速期慢性粒细胞性白血病的疗效观察.临床肿瘤学杂志,2000,5:263-265.
15.张日,支雅军,朱子玲,等.三氧化二砷联合木黄酮抑制CML细胞增殖的研究.江苏医药,2000,26:763-765.
16. Faderl S, Talpaz M, Estrov Z, et al. The biology of chronic myeloid leukemia. N Engl J Med, 1999, 341(3): 164-172.
17. Deininger MWN, Goldman JM, Melo JV. The molecular biology of chronic myeloid leukemia. Blood, 2000, 96: 3343-3356.
18. O'Dwyer ME, Mauro M J, Druker BJ. Recent advancements in the treatment of chronic myelogenous leukemia. Annu Rev Med, 2002, 53:369-381.
19. Gorre ME, Mohammed M, Ellwood K, et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science, 2001,293: 876-880.
20. Mahon FX, Deininger MW, Schultheis B, et al. Selection and characterization of BCR-ABL positive cell lines with differential sensitivity to the tyrosine kinase inhibitor STI571: diverse mechanisms of resistance. Blood, 2000, 96: 1070-1079.
21. O'Dwyer ME, Mauro MJ, Kuyl J, et al. Preliminary evaluation of the combination of imatinib mesylate(Gleevec) in combination with low dose interferon-alpha for the treatment of chronic phase CML. Blood, 2001 (suppl 1, abstr ), 98: 846a.
22. Rosti G, Trabacchi E, Bassi S, et al. Risk and early cytogenetic response to imatinib and interferon in chronic myeloid leukemia. Haematologica, 2003, 88: 256-259.
23. Guilhot F, Gardembas M, Rousselot P, et al. Imatinib in combination with cytarabine for the treatment of Philadelphia-postive chronic myelogenous leukemia chronic-phase patients : rational and design of phase Ⅰ/Ⅱ trials. Semin Hematol, 2003, 40: 92-97.
24. Thiesing JT, Ohno-Jones S, Kolibaba KS, et al. Efficacy of STI571, an abl tyrosine kinase inhibitor, in conjunction with other antileukemic agents against bcr-abl-positive cells. Blood, 2000, 96:3195-3199.
25. Perkins C, Kim CN, Fang G, et al. Arsenic induces apoptosis of multidrug-resistant human myeloid leukemia cells that express Bcr-Abl or overexpress, MDR, MRP, Bc1-2, or Bcl-x(L). Blood, 2000, 95: 1014-1022.
26. McGabon A, Bissonette R, Schmitt M, et al. bcr-abl maintains resistance of chronic myelogenous leukemia cells to apoptotic cell death. Blood, 1994, 83:1179-1187.
27. Cortez D, Stoica G,Pierce JH, et al. The BCR-ABL tyrosine kinase inhibits apoptosis by activating a Ras-dependent signaling pathway. Oncogene, 1996, 13: 2589-2594.
28. Amarante-mendes GP, Kim C, Liu L, et al. Bcr-Abl exerts its antiapoptotic effect against diverse apoptotic stimuli through blockage of mitochondrial release of cytochrome c and activation of caspase-3. Blood, 1998, 91:1700-1705.
29. La Rosee P, Johnson K, O'Dwyer ME, et al. In vitro studies of the combination of imatinib mesylate (Gleevec) and arsenic trioxide (Trisenox) in chronic myelogenous leukemia. Exp Hematol, 2002, 30: 729-737.
30. Zhang X, Subrahmanyam R, Wong R, et al. The NH2-terminal coiled-coil domain and tyrosine 177 Play important roles in induction of a myeloproliferative disease in mice by Bcr-Abl. Mol Cell Biol, 2001, 21(3): 840-853.
31. Zhang X, Wong R, Hao SX, et al. The SH2 domain of Bcr-Abl is not required to induce a murine myeloproliferative disease; however, SH2 signaling influences disease latency and phenotype. Blood, 2001, 97(1): 277-287.
32. Deininger MW, Vieira S, Mendiola R, et al. BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res, 2000, 60(7): 2049-2055.
33. Porosnicu M, Nimmanapalli R, Nguyen D, et al. Co-treatment with As_2O_3 enhances selective cytotoxic effects of STI-571 against Bcr-Abl-positive acute leukemia cells. Leukemia, 2001, 15: 772-778.
34. Damell JE, Kerr LM, Stark GR. Jak-STAT pathway and transcriptional activation in response to IFNs and other extracellular signaling protein. Science, 1994, 264: 1415-1421.
35. Ihle JN, Kerr IM. Jaks and Stats in signaling by the cytokine receptor superfamily. Trends Genet, 1995, 11 : 69-74.
36. Ihle JN. Signaling by the cytokine receptor superfamily in normal and transformed hematopoietic cells. Adv Cancer Res, 1996, 68: 23-65.
37. Ihle JN, Nosaka T, Thierfelder W, et al. Jaks and Stats in cytokine signaling. Stem Cells, 1997, 15(Suppl 1): 105-111.
38. Decker T, Kovarik P. Serine phosphorylation of STATs. Oncogene, 2000, 19(21): 2628-2637.
39. Bromberg J, Damell JE Jr. The role of STATs in transcriptional control and their impact on cellular function. Oncogene, 2000, 19(21): 2468-2473.
40. Levy DE, Lee CK. What does Stat3 do?. J Clin Invest, 2002, 109(9): 1143-1148.
41.扶云碧,张广森.BCR/ABL癌基因启动JAK/STAT信号转导途径的机制后果及意义.国外医学输血及血液学分册,2001,24(6):473-476.
42. Wilson-Rawls J, Liu J, Laneuville P. P210 Bcr-Abl interacts with the interleukin-3 beta c subunit and constitutively activates Jak2. Leukemia, 1997, 11(Suppl 3): 428-431.
43. Xie S, Wang Y, Liu JX, et al. Involvement of Jak2 tyrosine phosphorylation in Bcr-Abl transformation. Oncogene 2001, 20: 6188-6195.
44. Klejman A, Schreiner S J, Nieborowska-Skorska M, et al. The Src family kinase Hck couples BCR/ABL to STAT5 activation in myeloid leukemia cells. EMBO J, 2002, 21(21): 5766-5774.
45. Shuai K, Halpern J, ten Hoeve J, et al. Constitutive activation of STAT5 by the BCR-ABL oncogene in chronic myelogenous leukemia. Oncogene, 1996, 13(2): 247-54.
46. Ilaria RL Jr, Van Etten RA. P210 and P 190(BCR/ABL) induce the tyrosine phosphorylation and DNA binding activity of multiple specific STAT family members. J. Biol. Chem, 1996, 271(49): 31704-31710.
47. de Groot RP, Raaij makers JA, Lammers JW, et al. STAT5 activation by BCR-ABL contributes to transformation of K562 leukemia cells. Blood, 1999, 94(3): 1108-1112.
48. Sillaber C, Gesbert F, Frank DA, et al. STAT5 activation contributes to growth and viability in Bcr/Abl transformed cells. Blood, 2000, 95(6): 2118-2125.
49. Horita M, Andreu EJ, Benito A, et al. Blockade of the Bcr-Abl kinase activity induces apoptosis of chronic myelogenous leukemia cells by suppressing signal transducer and activator of transcription 5-dependent expression of Bcl-X_L. J Exp Med, 2000, 191(6): 977-984.
50. Jiang X, Lopez A, Holyoake T, et al. Autocrine production and action of IL-3 and granulocyte colony-stimulating factor in chronic myeloid leukemia. Proc Natl Acad Sci USA, 1999, 96(22): 12804-12809.
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