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砒霜和雄黄的现代故事（二）
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可以说，陈竺夫妇之所以能够在院士的神圣殿堂比翼双飞，很大程度受惠于砒霜和雄黄，分析他们取得如此成就的原因可能是：
（1）机遇垂青有准备的头脑：在改革开放之初，他们双双考上了血液学家王振义教授的研究生，而导师在此期间正好根据国际上采用诱导分化治疗白血病的设想，阴差阳错地利用上海的药厂只能合成出全反式维甲酸进行试验（原计划采用13顺式维甲酸），1985年首次用于急性早幼粒细胞白血病的治疗，获得满意结果，开创了将白血病细胞“改造”成接近“正常”细胞的先例（国外学者后来证明，13顺式维甲酸对白血病的疗效不佳）。
（2）国际视野让他们具备更高素养：陈竺曾回忆说，“1987年，我的导师王振义先生带领上海血液学研究所突破白血病分化治疗的方法，但在向国际一著名血液学期刊投稿时，论文被两次拒绝。第一次说结果令人怀疑，学术上有问题，第二次说英文写作有问题。当时，一位著名的美国血液学教授正在上海访问，他看了研究结果后觉得很不公正，于是按美国人的英文标准将论文重写了一遍，并要求该期刊务必接受，这样论文才得以发表。论文发表后即引起轰动，被誉为白血病治疗的‘中国革命’。”显然，王振义教授后来成为院士也与该论文的发表密切相关。而且，如前所述张亭栋和黄世林的成名也与陈竺夫妇的的工作和推荐有关。
（3）淘宝精神：我让学生搜索了陈竺夫妇发表的关于白血病的英文文献（附图），其中相当多的文献涉及中医药研究，所以陈竺院士自称为“中医迷”。记得当年他们对张亭栋的研究也是将信将疑，但当他们正式合作以后就发现，中药里面确实存在宝藏，于是一发而不可收。陈竺夫妇的贡献，是把三氧化二砷治疗急性早幼粒性白血病的效果推广介绍到国际上，并找到了三氧化二砷的治疗靶点，使三氧化二砷治疗白血病的研究国际化（其主要临床研究见表1。如今，研究证明三氧化二砷可通过诱导细胞分化和凋亡、降解PML—RARo、清除LIC、抑制肿瘤细胞增殖和抑制血管生成等多条途径发挥抗肿瘤作用，其中三氧化二砷和维甲酸分别作用于PML—RAR0的PML部分和RAR仅部分，协同降解PML—RARa而无交叉耐药，被认为是治疗APL最重要的分子机制，也是临床以ATRA+As2O3联合治疗APL的重要理论依据，树立了肿瘤靶向治疗的成功典范）。
附：陈竺夫妇发表的有关“白血病”研究文章（英文）
1. Zhen Tao，Wu Chuan-Feng，Liu Ping，Wu Hai-Yan，Zhou Guang Biao，Lu Ying，Liu Jian-Xiang， Liang Yang，Li Keqin Kathy，Wang Yue-Ying，Xie Yin-Yin，He Miao-Miao，Cao Huang-Ming， Zhang Wei-Na，Chen Li-Min，Petrie Kevin，Chen Sai-Juan，Chen Zhu. Targeting of AML1-ETO in t (8；21) Leukemia by Oridonin Generates a Tumor SuppressorLike Protein (Science Translational Medicine. 2012 Mar 28；4(127)：127ra38
2. Wang YY，Zhao LJ，Wu CF，Liu P，Shi L，Liang Y，Xiong SM，Mi JQ，Chen Z，Ren R，Chen SJ. C-KIT mutation cooperates with full-length AML1-ETO to induce acute myeloid leukemia in mice. Proc Natl Acad Sci U S A. 2011 Feb 8； 108(6)： 2450-5.
3. Zhou GB，Kang H，Wang L，Gao L，Liu P，Xie J，Zhang FX，Weng XQ，Shen ZX，Chen J， Gu LJ，Yan M，Zhang DE，Chen SJ，Wang ZY，Chen Z. Oridonin，a diterpenoid extracted from medicinal herbs，targets AML1 ETO fusion protein and shows potent antitumor activity with low adverse effects on t(8；21) leukemia in vitro and in vivo. Blood. 2007 Apr 15；109(8)：3441-50.
4. Wang YY，Zhou GB，Yin T，Chen B，Shi JY，Liang WX，Jin XL，You JH，Yang G，Shen ZX， Chen J，Xiong SM，Chen GQ，Xu F，Liu YW，Chen Z，Chen SJ. AML1-ETO and C-KIT mutation/overexpression in t(8；21) leukemia： implication in stepwise leukemogenesis and response to Gleevec. Proc Natl Acad Sci U S A. 2005 Jan 25；102(4)：1104-9.
5. Zhou GB，Chen SJ，Wang ZY，Chen Z. Back to the future of oridonin：again，compound from medicinal herb shows potent antileukemia efficacies in vitro and in vivo. Cell Res. 2007 Apr；17(4)：274-6.
6. Fang HT，Zhang B，Pan XF，Gao L，Zhen T，Zhao HX，Ma L，Xie J，Liu Z，Yu XJ，Cheng X，Feng TT，Zhang FX，Yang Y，Hu ZG，Sheng GQ，Chen YL，Chen SJ，Chen Z，Zhou GB. Bortezomib interferes with C-KIT processing and transforms the t (8；21)-generated fusion proteins into tumor-suppressing fragments in leukemia cells. Proc Natl Acad Sci U S A. 2012 Feb 14；109(7)：2521-6.
7. Ma LH，Liu H，Xiong H，Chen B，Zhang XW，Wang YY，Le HY，Huang QH，Zhang QH，Li BL， Chen Z，Chen SJ. Aberrant transcriptional regulation of the MLL fusion partner EEN by AML1-ETO and its implication in leukemogenesis. Blood. 2007 Jan 15；109(2)：769-77.
8. Wang L，Zhou GB，Liu P，Song JH，Liang Y，Yan XJ，Xu F，Wang BS，Mao JH，Shen ZX， Chen SJ，Chen Z. Dissection of mechanisms of Chinese medicinal formula Realgar-Indigo naturalis as an effective treatment for promyelocytic leukemia. Proc Natl Acad Sci U S A. 2008 Mar 25；105(12)：4826-31.
9. Mao JH，Sun XY，Liu JX，Zhang QY，Liu P，Huang QH，Li KK，Chen Q，Chen Z，Chen SJ. As4S4 targets RING-type E3 ligase c-CBL to induce degradation of BCR-ABL in chronic myelogenous leukemia. Proc Natl Acad Sci U S A. 2010 Dec 14；107(50)：21683-8.
10. Zhao LJ，Wang YY，Li G，Ma LY，Xiong SM，Weng XQ，Zhang WN，Wu B，Chen Z，Chen SJ. Functional features of RUNX1 mutants in acute transformation of chronic myeloid leukemia and their contribution to inducing murine full-blown leukemia. Blood. 2012 Mar 22；119(12)：2873-82.
11. Chen SJ，Zhou GB，Zhang XW，Mao JH，de Thé H，Chen Z. From an old remedy to a magic bullet： molecular mechanisms underlying the therapeutic effects of arsenic in fighting leukemia. Blood. 2011 Jun 16；117(24)：6425-37.
12. Zhou GB，Li G，Chen SJ，Chen Z. From dissection of disease pathogenesis to elucidation of mechanisms of targeted therapies：leukemia research in the genomic era. Acta Pharmacol Sin. 2007 Sep；28(9)：1434-49.
13. Hu J，Zhou GB，Wang ZY，Chen SJ，Chen Z. Mutant transcription factors and tyrosine kinases as therapeutic targets for leukemias： from acute promyelocytic leukemia to chronic myeloid leukemia and beyond. Adv Cancer Res. 2007；98：191-220.
14. Zhou GB，Zhang J，Wang ZY，Chen SJ，Chen Z. Treatment of acute promyelocytic leukaemia with all-trans retinoic acid and arsenic trioxide： a paradigm of synergistic molecular targeting therapy. Philos Trans R Soc Lond B Biol Sci. 2007 Jun 29；362(1482)：959-71.
15. Hu J，Liu YF，Wu CF，Xu F，Shen ZX，Zhu YM，Li JM，Tang W，Zhao WL，Wu W，Sun HP， Chen QS，Chen B，Zhou GB，Zelent A，Waxman S，Wang ZY，Chen SJ，Chen Z. Long-term efficacy and safety of all-trans retinoic acid/arsenic trioxide-based therapy in newly diagnosed acute promyelocytic leukemia. Proc Natl Acad Sci U S A. 2009 Mar 3；106(9)：3342-7.
16. Zhou GB，Zhao WL，Wang ZY，Chen SJ，Chen Z. Retinoic acid and arsenic for treating acute promyelocytic leukemia. PLoS Med. 2005 Jan；2(1)：e12.
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19. Zhou GB，Chen SJ，Chen Z. Acute promyelocytic leukemia：a model of molecular target based therapy. Hematology. 2005；10 Suppl 1：270-80.
20. Chen LJ，Dong Y，Chen SY，Zhang L，Zhou GB，Chen B，Wang L，Chen Z，Chen SJ. hCG-PLZF-RARalpha/hCG-RARalpha-PLZF transgenic mice developing into leukemia. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Dec；13(6)：924-31.
21. Hu Z，Pan XF，Wu FQ，Ma LY，Liu DP，Liu Y，Feng TT，Meng FY，Liu XL，Jiang QL，Chen XQ，Liu JL，Liu P，Chen Z，Chen SJ，Zhou GB. Synergy between proteasome inhibitors and imatinib mesylate in chronic myeloid leukemia. PLoS One. 2009 Jul 16；4(7)：e6257.
22. Liu H，Chen B，Xiong H，Huang QH，Zhang QH，Wang ZG，Li BL，Chen Z，Chen SJ. Functional contribution of EEN to leukemogenic transformation by MLL-EEN fusion protein. Oncogene. 2004 Apr 22；23(19)：3385-94.
23. Shen Y，Zhu YM，Fan X，Shi JY，Wang QR，Yan XJ，Gu ZH，Wang YY，Chen B，Jiang CL， Yan H，Chen FF，Chen HM，Chen Z，Jin J，Chen SJ. Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia. Blood. 2011 Nov 17；118(20)：5593-603.
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29. Jia PM，Zhu Q，Yu Y，Chen GQ，Chen SJ，Chen Z，Wang ZY，Tong JH. Experimental study of low dose arsenic trioxide in treatment of patients with acute promyelocytic leukemia. Ai Zheng. 2002 Apr；21(4)：337-40. Chinese
30. Yan XJ，Xu J，Gu ZH，Pan CM，Lu G，Shen Y，Shi JY，Zhu YM，Tang L，Zhang XW，Liang WX，Mi JQ，Song HD，Li KQ，Chen Z， Chen SJ. Exome sequencing identifies somatic mutations of DNA methyltransferase gene DNMT3A in acute monocytic leukemia. Nat Genet. 2011 Mar 13；43(4)：309-15.
31. Wang LN，Pan Q，Fu JF，Shi JY，Jin J，Li JM，Hu J，Zhao WL，Chen Z，Chen SJ. FIP1L1-PDGFRalpha alone or with other genetic abnormalities reveals disease progression in chronic eosinophilic leukemia but good response to imatinib. Chin Med J (Engl). 2008 May 20；121(10)：867-73.
32. Liu YF，Shen ZX，Chen X，Wang AH，Cao Q，Zhu YM，Chen SJ，Chen Z，Wang ZY. Clinical observation of the short-term efficacy of the treatment with combination of all-trans retinoic acid (ATRA) and arsenic trioxide (As2O3) in newly diagnosed acute promyelocytic leukemia (APL). Zhonghua Xue Ye Xue Za Zhi. 2003 Jan；24(1)：25-7. Chinese.
33. Chen Z，Chen GQ，Shen ZX，Sun GL，Tong JH，Wang ZY，Chen SJ. Expanding the use of arsenic trioxide： leukemias and beyond. Semin Hematol. 2002 Apr；39(2 Suppl 1)：22-6.
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35. Zhou T，Wang L，Zhu KY，Dong M，Xu PF，Chen Y，Chen SJ，Chen Z，Deng M，Liu TX. Dominant-negative C/ebpα and polycomb group protein Bmi1 extend short-lived hematopoietic stem/progenitor cell life span and induce lethal dyserythropoiesis. Blood. 2011 Oct 6；118(14)：3842-52.
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37. Zhang NN，Shen SH，Jiang LJ，Zhang W，Zhang HX，Sun YP，Li XY，Huang QH，Ge BX， Chen SJ，Wang ZG，Chen Z，Zhu J. RIG-I plays a critical role in negatively regulating granulocytic proliferation. Proc Natl Acad Sci U S A. 2008 Jul 29；105(30)：10553-8.
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39. Zhu Q，Zhang JW，Zhu HQ，Shen YL，Flexor M，Jia PM，Yu Y，Cai X，Waxman S，Lanotte M，Chen SJ，Chen Z，Tong JH. Synergic effects of arsenic trioxide and cAMP during acute promyelocytic leukemia cell maturation subtends a novel signaling cross-talk. Blood. 2002 Feb 1；99(3)：1014-22.
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43. Fu CT，Zhu KY，Mi JQ，Liu YF，Murray ST，Fu YF，Ren CG，Dong ZW，Liu YJ，Dong M， Jin Y，Chen Y，Deng M，Zhang W，Chen B，Breslin P，Chen SJ，Chen Z，Becker MW，Zhu J，Zhang JW，Liu TX. An evolutionarily conserved PTEN-C/EBPalpha-CTNNA1 axis controls myeloid development and transformation. Blood. 2010 Jun 10；115(23)：4715-24.
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46. Wang ZY，Chen Z. Acute promyelocytic leukemia： from highly fatal to highly curable. Blood. 2008 Mar 1；111(5)：2505-15.
47. Chen GQ，Zhou L，Styblo M，Walton F，Jing Y，Weinberg R，Chen Z，Waxman S. Methylated metabolites of arsenic trioxide are more potent than arsenic trioxide as apoptotic but not differentiation inducers in leukemia and lymphoma cells. Cancer Res. 2003 Apr 15；63(8)：1853-9.
48. Wang K，Wang P，Shi J，Zhu X，He M，Jia X，Yang X，Qiu F，Jin W，Qian M，Fang H， Mi J，Yang X，Xiao H，Minden M，Du Y，Chen Z，Zhang J. PML/RARalpha targets promoter regions containing PU.1 consensus and RARE half sites in acute promyelocytic leukemia. Cancer Cell. 2010 Feb 17；17(2)：186-97.
49. Song MG， Gao SM， Du KM， Xu M， Yu Y， Zhou YH， Wang Q， Chen Z， Zhu YS， Chen GQ. Nanomolar concentration of NSC606985， a camptothecin analog， induces leukemic-cell apoptosis through protein kinase Cdelta-dependent mechanisms. Blood. 2005 May 1；105(9)：3714-21.
50. Du Y，Wang K，Fang H，Li J，Xiao D，Zheng P，Chen Y，Fan H，Pan X，Zhao C，Zhang Q，Imbeaud S，Graudens E，Eveno E，Auffray C，Chen S，Chen Z，Zhang J. Coordination of intrinsic， extrinsic， and endoplasmic reticulum-mediated apoptosis by imatinib mesylate combined with arsenic trioxide in chronic myeloid leukemia. Blood. 2006 Feb 15；107(4)：1582-90.
51. Zhao KW，Li X，Zhao Q，Huang Y，Li D，Peng ZG，Shen WZ，Zhao J，Zhou Q，Chen Z， Sims PJ，Wiedmer T，Chen GQ. Protein kinase Cdelta mediates retinoic acid and phorbol myristate acetate-induced phospholipid scramblase 1 gene expression： its role in leukemic cell differentiation. Blood. 2004 Dec 1；104(12)：3731-8.
52. Xiao DK，Du YZ，Fan HY，Chen YL，Chen Z，Zhang J，Wang KK. Mechanisms of fenretinide-triggered apoptosis in leukemic cells. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Dec；13(6)：975-8. Chinese.
53. Meng X，Cheng G，Cao W，Zhu J，Chen J，Chen Z，Chen S. Development of Acute Promyelocytic Leukemia in PML-RARalpha Transgenic Mice. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2000 Jun；8(2)：104-109. Chinese.
54. e Thé H，Chen Z. Acute promyelocytic leukaemia： novel insights into the mechanisms of cure. Nat Rev Cancer. 2010 Nov；10(11)：775-83.
55. Chen SJ，Zhou GB. Targeted therapy： The new lease on life for acute promyelocytic leukemia， and beyond. IUBMB Life. 2012 Aug；64(8)：671-5.
56. Zhen T，Chen SJ. Progress on targeted therapy of acute myeloid leukemia with active components of Chinese herbal medicines. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009 Jan；29(1)：14-8. Chinese.
57. Yang HT，Wu DH，Xue XY，Liang WX，Miao XY，Pang H，Chen SJ. Cloning，expression， purification and crystallization of NHR3 domain from acute myelogenous leukemia-related protein AML1-ETO. Acta Biochim Biophys Sin (Shanghai). 2004 Aug；36(8)：566-70.
58. Chen SJ，Chen LJ，Zhou GB. Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Feb；13(1)：1-8. Chinese.
59. Zhen T，Chen SJ. Progress on targeted therapy of acute myeloid leukemia with active components of Chinese herbal medicines. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009 Jan；29(1)：14-8. Chinese.
60. Shi L，Wang YY，Chen SJ. Recent progress of study on retroviral mediated mouse model of myeloid leukemia --review. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Aug；19(4)：1058-63.
61. Shi WY，Wang L，Xiao D，Yao Y，Yang F，Jiang XX，Leboeuf C，Janin A，Chen SJ，Zhao WL. Proteasome inhibitor bortezomib targeted tumor-endothelial cell interaction in T-cell leukemia/lymphoma. Ann Hematol. 2011 Jan；90(1)：53-8.
62. Wang QR，Shi JY，Shi L，Chen SJ. Mutational detection of full-length mixed lineage leukemia gene in patients with de novo AML-M4 and M5. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2012 Feb；20(1)：12-7
63. Wang L，Shi WY，Yang F，Tang W，Gapihan G，Varna M，Shen ZX，Chen SJ，Leboeuf C， Janin A，Zhao WL. Bevacizumab potentiates chemotherapeutic effect on T-leukemia/lymphoma cells by direct action on tumor endothelial cells. Haematologica. 2011 Jun；96(6)：927-31.
64. Wang Y，Gu MM，Tan Y，Lu SY，Wang L，Kong H，Sun YP，Lu ZY，Chen SJ，Wang ZY， Wang ZG. Development of human myeloid leukemia-like phenotype in NUP98-PMX1 transgenic mice. Zhonghua Xue Ye Xue Za Zhi. 2004 May；25(5)：262-5. Chinese
65. Chen SJ. Mutation associations in RA-defiant APL. Blood. 2012 Sep 6；120(10)：1969-70.
66. Dong S，Chen SJ，Tweardy DJ. Cross-talk between retinoic acid and STAT3 signaling pathways in acute promyelocytic leukemia. Leuk Lymphoma. 2003 Dec；44(12)：2023-9. Review.
67. Chen SJ，Zhou GB. Targeted therapy： The new lease on life for acute promyelocytic leukemia，and beyond. IUBMB Life. 2012 Aug；64(8)：671-5.
68. Zhen T，Chen SJ. Progress on targeted therapy of acute myeloid leukemia with active components of Chinese herbal medicines. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009 Jan；29(1)：14-8. Chinese.
69. Yang HT，Wu DH，Xue XY，Liang WX，Miao XY，Pang H，Chen SJ. Cloning，expression， purification and crystallization of NHR3 domain from acute myelogenous leukemia-related protein AML1-ETO. Acta Biochim Biophys Sin (Shanghai). 2004 Aug；36(8)：566-70.
70. Chen SJ，Chen LJ，Zhou GB. Basic and clinical studies of the gene product-targeting therapy based on leukemogenesis--editorial. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2005 Feb；13(1)：1-8. Chinese.
71. Zhen T，Chen SJ. Progress on targeted therapy of acute myeloid leukemia with active components of Chinese herbal medicines. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2009 Jan；29(1)：14-8. Chinese.
72. Shi L，Wang YY，Chen SJ. Recent progress of study on retroviral mediated mouse model of myeloid leukemia -- review. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2011 Aug；19(4)：1058-63.
73. Shi WY，Wang L，Xiao D，Yao Y，Yang F，Jiang XX，Leboeuf C，Janin A，Chen SJ，Zhao WL. Proteasome inhibitor bortezomib targeted tumor-endothelial cell interaction in T-cell leukemia/lymphoma. Ann Hematol. 2011 Jan；90(1)：53-8.
74. Wang QR，Shi JY，Shi L，Chen SJ. Mutational detection of full-length mixed lineage leukemia gene in patients with de novo AML-M4 and M5. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2012 Feb；20(1)：12-7
75. Wang L，Shi WY，Yang F，Tang W，Gapihan G，Varna M，Shen ZX，Chen SJ，Leboeuf C， Janin A，Zhao WL. Bevacizumab potentiates chemotherapeutic effect on T-leukemia/lymphoma cells by direct action on tumor endothelial cells. Haematologica. 2011 Jun；96(6)：927-31.
76. Wang Y，Gu MM，Tan Y，Lu SY，Wang L，Kong H，Sun YP，Lu ZY，Chen SJ，Wang ZY，Wang ZG. Development of human myeloid leukemia-like phenotype in NUP98-PMX1 transgenic mice. Zhonghua Xue Ye Xue Za Zhi. 2004 May；25(5)：262-5. Chinese
77. Chen SJ. Mutation associations in RA-defiant APL. Blood. 2012 Sep 6；120(10)：1969-70.
78. Dong S，Chen SJ，Tweardy DJ. Cross-talk between retinoic acid and STAT3 signaling pathways in acute promyelocytic leukemia. Leuk Lymphoma. 2003 Dec；44(12)：2023-9. Review.
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