Research Areas:

Dr. Wang’s research focuses on understanding the pathogenesis of hematological malignancies and stem cell studies. In particular, Dr. Wang is interested in identifying the genes that are disrupted in these disorders, and developing the new therapeutic strategies for patients with these diseases. Blood cells are generated by hematopoietic stem cells, which are proposed to be the cell of origin in leukemia and we are studying how their behavior goes awry when the cells become transformed. Cancer stem cells show loss of normal growth control mechanisms, leading to abnormal cell division, survival and expansion. The development of hematological malignancies is commonly associated with aberrant transcriptional regulation, where genes are inappropriately turned on or off. In most cases, correcting these abnormalities would block the development or progression of hematological malignancies in patients.

Brief Biography:

2017 - Present: Professor, Principal Investigator, Shanghai Institute of Nutrition and Health, CAS

2015 - 2016: Professor,Principal Investigator, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine

2013-2015: Assistant Professor, Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami

2010-2012: Research Associate, Memorial Sloan - Kettering Cancer Center

2008-2010: Research Fellow, Memorial Sloan - Kettering Cancer Center

2002-2007: Institute of Health Sciences, Shanghai Institute of Life Science, Chinese Academy of Science, Ph.D.

1998-2002: Fudan University, Bachelor

Selected Publications: (*Corresponding Author)

1. Ming-Yue Fei, Yong Wang, Bin-He Chang, Kai Xue, Fangyi Dong, Dan Huang, Xi-Ya Li, Zi-Juan Li, Cheng-Long Hu, Ping Liu, Ji-Chuan Wu, Peng-Cheng Yu, Ming-Hua Hong, Shu-Bei Chen, Chun-Hui Xu, Bing-Yi Chen, Yi-Lun Jiang, Na Liu, Chong Zhao, Jia-Cheng Jin, Dan Hou, Xin-Chi Chen, Yi-Yi Ren, Chu-Han Deng, Jia-Ying Zhang, Li-juan Zong, Rou-Jia Wang, Fei-Fei Gao, Hui Liu, Qun-Ling Zhang, Ling-Yun Wu, Jinsong Yan, Shuhong Shen, Chun-Kang Chang, Xiao-Jian Sun, Lan Wang*. The cell non-autonomous function of ID1 promotes AML progression via ANGPTL7 from the microenvironment. Blood 2023 Jun 15;blood.2022019537.
2. Dan Liu, Chun-Hui Xu, Yan-Ting Liu, Wen Ouyang, Shao-Jian Lin, Ai-Ning Xu, Yuan-Liang Zhang, Yin-Yin Xie, Qiu-Hua Huang, Wei-Li Zhao, Zhu Chen, Lan Wang, Sai-Juan Chen*, Jin-Yan Huang*, Zhe-Bao Wu*, Xiao-Jian Sun*. A systematic survey of LU domain-containing proteins reveals a novel human gene, LY6A, which encodes the candidate ortholog of mouse Ly-6A/Sca-1 and is aberrantly expressed in pituitary tumor. Front Med 2023 Jun;17(3):458-475.
3. Roujia Wang^#, Youshan Zhao^#, Zijuan Li^#, Juan Guo, Sida Zhao, Luxi Song, Dong Wu, Lan Wang*, Chunkang Chang*. S100a9 deficiency accelerates MDS associated tumor escape via PD-1/PD-L1 overexpression. Acta Biochimica et Biophysica Sinica 2023 Feb 25;55(2):194-201.
4. Xi-Ya Li^#, Ji-Chuan Wu^#, Ping Liu^#, Zi-Juan Li, Yong Wang, Bing-Yi Chen, Cheng-Long Hu, Ming-Yue Fei, Peng-Cheng Yu, Yi-Lun Jiang, Chun-Hui Xu, Bin-He Chang, Xin-Chi Chen, Li-Juan Zong, Jia-Ying Zhang, Ying Fang, Xiao-Jian Sun, Kai Xue, Li Wang, Shu-Bei Chen, Shi-Yu Jiang, Ai-ling Gui, Ling Yang, Juan J. Gu, Bao-Hua Yu, Qun-ling Zhang*, Lan Wang*. Inhibition of USP1 reverses the chemotherapy resistance through destabilization of MAX in the relapsed/refractory B cell lymphoma. Leukemia 2023 Jan;37(1):164-177.
5. Cheng-Long Hu, Bing-Yi Chen, Zijuan Li, Tianbiao Yang, Chun-Hui Xu, Ruirui Yang, Peng-Cheng Yu, Jingyao Zhao, Ting Liu, Na Liu, Bin Shan, Qunling Zhang, Junhong Song, Ming-Yue Fei, Li-Juan Zong, Jia-Ying Zhang, Ji-Chuan Wu, Shu-Bei Chen, Yong Wang, Binhe Chang, Dan Hou, Ping Liu, Yilun Jiang, Xiya Li, Xinchi Chen, Chu-Han Deng, Yi-Yi Ren, Roujia Wang, Jiacheng Jin, Kai Xue, Ying Zhang, Meirong Du, Jun Shi, Ling-Yun Wu, Chun-Kang Chang, Shuhong Shen, Zhu Chen, Sai-Juan Chen, Xiaolong Liu*, Xiao-Jian Sun*, Mingyue Zheng*, Lan Wang*. Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia. Cell Res 2022 Dec;32(12):1105-1123.
6. Yi-Fan Zhang, Xiao-Lin Wang, Chun-Hui Xu, Na Liu, Ling Zhang, Yu-Ming Zhang, Yin-Yin Xie, Yuan-Liang Zhang, Qiu-Hua Huang, Lan Wang, Zhu Chen, Sai-Juan Chen, Robert G Roeder, Shuhong Shen, Kai Xue, Xiao-Jian Sun*. A direct comparison between AML1-ETO and ETO2-GLIS2 leukemia fusion proteins reveals context-dependent binding and regulation of target genes and opposite functions in cell differentiation. Front Cell Dev Biol 2022 Sep 7;10:992714.
7. Meijuan Bai, Peijuan Cao, Yijun Lin, Pengcheng Yu, Shuo Song, Lingling Chen, Lan Wang, Yan Chen*. Intermittent Caloric Restriction Promotes Erythroid Development and Ameliorates Phenylhydrazine-Induced Anemia in Mice. Front Nutr 2022 Jun 9;9:892435.
8. Jinxi Li, James D Glover, Haiguo Zhang, Meifang Peng, Jingze Tan, Chandana Basu Mallick, Dan Hou, Yajun Yang, Sijie Wu, Yu Liu, Qianqian Peng, Shijie C Zheng, Edie I Crosse, Alexander Medvinsky, Richard A Anderson, Helen Brown, Ziyu Yuan, Shen Zhou, Yanqing Xu, John P Kemp, Yvonne Y W Ho, Danuta Z Loesch, Lizhong Wang, Yingxiang Li, Senwei Tang, Xiaoli Wu, Robin G Walters, Kuang Lin, Ruogu Meng, Jun Lv, Jonathan M Chernus, Katherine Neiswanger, Eleanor Feingold, David M Evans, Sarah E Medland, Nicholas G Martin, Seth M Weinberg, Mary L Marazita, Gang Chen, Zhengming Chen, Yong Zhou, Michael Cheeseman, Lan Wang, Li Jin, Denis J Headon, Sijia Wang*. Limb development genes underlie variation in human fingerprint patterns. Cell 2022 Jan 6;185(1):95-112.
9. Fan Zhang, Qi-Yu Zeng, Hao Xu, Ai-Ning Xu, Dian-Jia Liu, Ning-Zhe Li, Yi Chen, Yi Jin , Chun-Hui Xu, Chang-Zhou Feng, Yuan-Liang Zhang, Dan Liu, Na Liu, Yin-Yin Xie, Shan-He Yu, Hao Yuan, Kai Xue, Jing-Yi Shi, Ting Xi Liu, Peng-Fei Xu, Wei-Li Zhao, Yi Zhou, Lan Wang, Qiu-Hua Huang, Zhu Chen, Sai-Juan Chen*, Xiao-Long Zhou*, Xiao-Jian Sun*. Selective and competitive functions of the AAR and UPR pathways in stress-induced angiogenesis. Cell Discov 2021 Oct 26;7(1):98.
10. Kai Xue^#, Ji-Chuan Wu^#, Xi-Ya Li^#, Ran Li^#, Qun-ling Zhang, Jin-Jia Chang, Yi-Zhen Liu, Chun-Hui Xu, Jia-Ying Zhang, Xiao-Jian Sun, Juan J. Gu, Wei-Jian Guo*, Lan Wang*. Chidamide triggers BTG1-mediated autophagy and reverses the chemotherapy resistance in the relapsed/refractory B-cell lymphoma. Cell Death Dis 2021 Oct 1;12(10):900.
11. Dian-Jia Liu^#, Fan Zhang^#, Yi Chen^#, Yi Jin, Yuan-Liang Zhang, Shu-Bei Chen, Yin-Yin Xie, Qiu-Hua Huang, Wei-Li Zhao, Lan Wang, Peng-Fei Xu, Zhu Chen, Sai-Juan Chen, Bing Li, Aijun Zhang, Xiao-Jian Sun*. Setd2 knockout zebrafish is viable and fertile: differential and developmental stress-related requirements for Setd2 and histone H3K36 trimethylation in different vertebrate animals. Cell Discov 2020 Oct 20;6:72.
12. Bing-Yi Chen^#, Jun-Hong Song^#, Cheng-Long Hu^#, Shu-Bei Chen, Qunling Zhang, Chun-Hui Xu, Ji-Chuan Wu, Dan Hou, Dr. Ming Sun, Yuan-Liang Zhang, Na Liu, Peng-Cheng Yu, Ping Liu, Li-juan Zong, Jia-Ying Zhang, Ruo-fei Dai, Dr. Fei Lan, Qiuhua Huang, Sujiang Zhang, Stephen D Nimer, Prof. Zhu Chen, Prof. Sai-Juan Chen, Xiao-Jian Sun*, Lan Wang*. SETD2 deficiency accelerates MDS-associated leukemogenesis via S100a9 in NHD13 mice and predicts poor prognosis in MDS. Blood 2020 Jun 18;35(25):2271-2285.
13. Ye Xu, Na Man, Daniel Karl, Concepcion Martinez, Fan Liu, Jun Sun, Camilo Jose Martinez, Gloria Mas Martin, Felipe Beckedorff, Fan Lai, Jingyin Yue, Alejandro Roisman, Sarah Greenblatt, Stephanie Duffort, Lan Wang, Xiaojian Sun, Maria Figueroa, Ramin Shiekhattar*, Stephen Nimer*. TAF1 plays a critical role in AML1-ETO driven leukemogenesis. Nat Commun 2019 Oct 29;10(1):4925.
14. Meng-Meng Zhang^#, Na Liu^#, Yuan-Liang Zhang^#, Bowen Rong, Xiao-Lin Wang, Chun-Hui Xu, Yin-Yin Xie, Shuhong Shen, Jiang Zhu, Stephen D. Nimer, Zhu Chen, Sai-Juan Chen, Robert G. Roeder, Fei Lan, Lan Wang*, Qiu-Hua Huang*, Xiao-Jian Sun*. Destabilization of AETFC through C/EBPα-mediated repression of LYL1 contributes to t(8,21) leukemic cell differentiation. Leukemia 2019 Jul;33(7):1822-1827.
15. Liu Na^#, Song Junhong^#, Xie Yangyang^#, Wang Xiaolin, Rong Bowen, Man Na, Zhang Mengmeng, Zhang Qunling, Gao Feifei, Du Meirong, Zhang Ying, Shen Jian, Xu Chunhui, Hu Chenglong, Wu Jichuan, Liu Ping, Zhang Yuanliang, Xie Yinyin, Liu Ping, Huang Jinyan, Huang Qiuhua, Lan Fei, Shen Shuhong, Nimer Stephen D, Chen Zhu, Chen Saijuan, Roeder Robert G*, Wang Lan*, Sun Xiaojian*. Different roles of E proteins in t(8;21) leukemia: E2-2 compromises the function of AETFC and negatively regulates leukemogenesis. Proc Natl Acad Sci U S A 2019 Jan 15;116(3):890-899.
16. Yuan-Liang Zhang, Jie-Wen Sun, Yin-Yin Xie, Yan Zhou, Ping Liu, Jia-Chun Song, Chun-Hui Xu, Lan Wang, Dan Liu, Ai-Ning Xu, Zhu Chen, Sai-Juan Chen, Xiao-Jian Sun*, Qiu-Hua Huang*. Setd2 deficiency impairs hematopoietic stem cell self-renewal and causes malignant transformation. Cell Res 2018 Apr;28(4):476-490.
17. Yun-Chi Tang*, Hui Yuwen, Kai-Ying Wang, Peter M. Bruno, Kevin Bullock, Amy Deik, Stefano Santaguida, Marianna Trakala, Sarah J. Pfau, Na Zhong, Tao Huang, Lan Wang, Clary B. Clish, Michael T. Hemann, Angelika Amon*. Aneuploid Cell Survival Relies upon Sphingolipid Homeostasis. Cancer Res 2017 Oct 1;77(19):5272-5286.
18. Jian-Ping Li, Fu-Hong He, Peng Zhang, Shi Chen, Hui Shi, Yan-Ling Sun, Ying Guo, Hui Yang, Na Man, Sarah Greenblatt, Zhaomin Li, Zhengyu Guo, Yuan Zhou, Lan Wang, Lluis Morey, Sion Williams, Xi Chen, Qun-Tian Wang, Stephen D. Nimer, Peng Yu, Qian-Fei Wang*, Ming-Jiang Xu*, Feng-Chun Yang*. Loss of Asxl2 leads to myeloid malignancies in mice. Nat Commun 2017 Jun 8;8:15456.
19. G Cheng, F Liu, T Asai, F Lai, N Man, H Xu, S Chen, S Greenblatt, P-J Hamard, K Ando, X Chen, L Wang, C Martinez, M Tadi, L Wang, M Xu, F-C Yang, R Shiekhattar, S D Nimer. Loss of p300 accelerates MDS-associated leukemogenesis. Leukemia 2017 Jun;31(6):1382-1390.
20. Na Man, Yurong Tan, Xiaojian Sun, Fan Liu, Guoyan Cheng, Sarah Greenblatt, Camilo Martinez, Daniel L. Karl, Koji Ando, Ming Sun, Dan Hou, Bingyi Chen, Mingjiang Xu, Fengchun Yang, Zhu Chen, Saijuan Chen, Stephen D. Nimer*, Lan Wang*. Caspase-3 controls AML1-ETO-driven leukemogenesis via autophagy modulation in a ULK1 dependent manner. Blood 2017 May 18;129(20):2782-2792.
21. Fan Liu, Lan Wang, Fabiana Perna, Stephen D. Nimer*. Beyond transcription factors: how oncogenic signaling reshapes the epigenetic landscape. Nature Reviews Cancer 2016 Jun;16(6):359-372.
22. Kotaro Shirakawa, Lan Wang, Na Man, Jasna Maksimoska, Alexander W. Sorum, Hyung W. Lim, Intelly S. Lee, Tadahiro Shimazu, John C. Newman, Sebastian Schr？der, Melanie Ott, Ronen Marmorstein, Jordan Meier, Stephen D. Nimer, Eric Verdin*. Salycylate, diflunisal and their metabolites inhibit CBP/p300 and exhibit anticancer activity. Elife 2016 May 31;5.
23. Na Man, Xiao-Jian Sun, Yurong Tan, Marta García-Cao, Fan Liu, Guo-Yan Cheng, Megan Hatlen, Haiming Xu, Ronit Shah, Nolan Chastain, Na Liu, Gang Huang, Yuan Zhou, Mengyao Sheng, Jun-Hong Song, Feng-Chun Yang, Robert Benezra, Stephen D. Nimer*, Lan Wang*. Differential role of Id1 in MLL-AF9-driven leukemia based on cell of origin. Blood 2016 May 12;127(19):2322-2326.
24. Megan A. Hatlen, Kanika Arora, Vladimir Vacic, Ewa A. Grabowska, Willey Liao, Bridget Riley-Gillis, Dayna M. Oschwald, Lan Wang, Jacob E. Joergens, Alan H. Shih, Franck Rapaport, Sheng-Qing Gu, Francesca Voza, Takashi Asai, Benjamin G. Neel, Michael G. Kharas, Mithat Gonen, Ross L. Levine, Stephen D. Nimer*. Integrative analysis of the mutational landscape of mouse and human AML identifies functionally relevant leukemia disease alleles. J Exp Med 2016 Jan 11;213(1):25-34.
25. Lan Wang, Pierre-Jacques Hamard, Stephen D Nimer*. PARP inhibitors: a treatment option for AML? Nat Med 2015 Dec;21(12):1393-1394.
26. Fan Liu, Guoyan Cheng, Pierre-Jacques Hamard, Sarah Greenblatt, Lan Wang, Na Man, Fabiana Perna, Haiming Xu, Madhavi Tadi, Luisa Luciani, Stephen D. Nimer*. Arginine methyltransferase PRMT5 is essential for sustaining normal adult hematopoiesis. J Clin Invest 2015 Sep;125(9):3532-3544.
27. Lan Wang*, Na Man, Xiao-Jian Sun, Yu-Rong Tan, Marta Garcia Cao, Fan Liu, Megan Hatlen, Haiming Xu, Gang Huang, Meredith Mattlin, Arpit Mehta, Evadnie Rampersaud, Robert Benezra, Stephen D. Nimer. Regulation of AKT signaling by Id1 controls t(8,21) leukemia initiation and progression. Blood 2015 Jul 30;126(5):640-650.
28. Xiao-Jian Sun, Na Man, Yurong Tan, Stephen D. Nimer, Lan Wang*. The Role of Histone Acetyltransferases in Normal and Malignant Hematopoiesis. Front Oncol 2015 May 26;5:108.
29. Ly P. Vu, Fabiana Perna, Lan Wang, Francesca Voza, Maria E. Figueroa, Paul Tempst, Hediye Erdjument-Bromage, Rui Gao, Si-Si Chen, Elisabeth Paietta, Tony Deblasio, Ari Melnick, Yan Liu, Xin-Yang Zhao, Stephen D. Nimer*. PRMT4 blocks myeloid differentiation by assembling a methyl-RUNX1-dependent repressor complex. Cell Reports 2013 Dec 26;5(6):1625-1638.
30. Megan A. Hatlen, Lan Wang, Stephen D. Nimer*. AML1-ETO driven acute leukemia: insights into pathogenesis and potential therapeutic approaches. Front Med 2012 Sep;6(3):248-262.
31. Xiao-Jian Sun, Zhan-Xin Wang, Lan Wang, Yanwen Jiang, Nils Kost, T. David Soong, Wei-Yi Chen, Zhan-Yun Tang, Tomoyoshi Nakadai, Olivier Elemento, Wolfgang Fischle, Ari Melnick, Dinshaw J. Patel, Stephen D. Nimer, Robert G. Roeder*. A stable transcription factor complex nucleated by oligomeric AML1-ETO controls leukaemogenesis. Nature 2013 Aug 1;500(7460):93-97.
32. Gang Huang*, Xing-Hui Zhao, Lan Wang, Shannon Elf, Hao Xu, Xinyang Zhao, Goro Sashida, Yue Zhang, Yan Liu, Jennifer Lee, Silvia Menendez, Youyang Yang, Xiaomei Yan, Pu Zhang, Daniel G. Tenen, Motomi Osato, James J.-D. Hsieh, Stephen D. Nimer*. The ability of MLL to bind RUNX1 and methylate H3K4 at PU.1 regulatory regions is impaired by MDS/AML-associated RUNX1/AML1 mutations. Blood 2011 Dec 15;118(25):6544-6552.
33. Lan Wang, Alexander Gural, Xiao-Jian Sun, Xin-Yang Zhao, Fabiana Perna, Gang Huang, Megan A. Hatlen, Ly Vu, Fan Liu, Hai-Ming Xu, Takashi Asai, Hao Xu, Tony Deblasio, Silvia Menendez, Francesca Voza, Yan-Wen Jiang, Philip A. Cole, Jin-Song Zhang, Ari Melnick, Robert G. Roeder, Stephen D. Nimer*. The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation. Science 2011 Aug 5;333(6043):765-769.
34. Fan Liu, Xin-Yang Zhao, Fabiana Perna, Lan Wang, Priya Koppikar, Omar Abdel-Wahab, Michael W. Harr, Ross L. Levine, Hao Xu, Ayalew Tefferi, Anthony Deblasio, Megan Hatlen, Silvia Menendez, Stephen D. Nimer*. JAK2V617F-mediated phosphorylation of PRMT5 downregulates its methyltransferase activity and promotes myeloproliferation. Cancer Cell 2011 Feb 15;19(2):283-294.
35. Fabiana Perna, Nadia Gurvich, Ruben Hoya-Arias, Omar Abdel-Wahab, Ross L. Levine, Takashi Asai, Francesca Voza, Silvia Menendez, Lan Wang, Fan Liu, Xin-Yang Zhao, Stephen D. Nimer*. Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q- polycythemia vera. Blood 2010 Oct 14;116(15):2812-2821.
36. Yi-Wen Zhang, Xiao-Xing Jiang, Qiu-Sheng Chena, Wen-Yu Shia, Lan Wang, Han-Dong Sun, Zhi-Xiang Shen, Zhu Chen, Sai-Juan Chen, Wei-Li Zhao*. Eriocalyxin B induces apoptosis in lymphoma cells through multiple cellular signaling pathways. Exp Hematol 2010 Mar;38(3):191-201.
37. Lan Wang, Gang Huang, Xinyang Zhao, Megan A. Hatlen, Ly Vu, Fan Liu, Stephen D. Nimer*. Post-translational modifications of Runx1 regulate its activity in the cell. Blood Cells Mol Dis 2009 Jul-Aug;43(1):30-34.
38. Lan Wang, Guang-Biao Zhou, Ping Liu, Jun-Hong Song, Yang Liang, Xiao-Jing Yan, Fang Xu, Bing-Shun Wang, Jian-Hua Ma, Zhi-Xiang Shen, Sai-Juan Chen*, Zhu Chen*. 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):4826-4831.
39. Wei-Li Zhao^#, Lan Wang^#, Yuan-Hua Liu^#, Jin-Song Yan^#, Christophe Leboeuf, Yan-Yan Liu, Wei-Li Wu, Anne Janinc, Zhu Chen, Sai-Juan Chen*. Combined effects of histone deacetylase inhibitor and rituximab on non-Hodgkin's B-lymphoma cells apoptosis. Exp Hematol 2007 Dec;35(12):1801-1811.
40. Guang-Biao Zhou^#, Hui Kang^#, Lan Wang^#, Li Gao, Ping Liu, Jun Xie, Feng-Xiang Zhang, Xiang-Qin Weng, Zhi-Xiang Shen, Jue Chen, Long-Jun Gu, Ming Yan, Dong-Er Zhang, Sai-Juan Chen, Zhen-Yi Wang, Zhu Chen*. 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):3441-3450.
41. Lan Wang, W-L Zhao, J-S Yan, P Liu, H-P Sun, G-B Zhou, Z-Y Weng, W-L Wu, X-Q Weng, X-J Sun, Z Chen*, H-D Sun*, S-J Chen*. Eriocalyxin B induces apoptosis of t(8,21) leukemia cells through NF-kappaB and MAPK signaling pathways and triggers degradation of AML1-ETO oncoprotein in a caspase-3-dependent manner. Cell Death Differ 2007 Feb;14(2):306-317.
42. Lan Wang, Sai-Juan Chen. Monoclonal antibodies treat hematopoietic malignancies. Shanghai: Shanghai Science and Technology Press 2006 pp.309-322.
43. Xiao-Jian Sun, Ju Wei, Xin-Yan Wu, Ming Hu, Lan Wang, Hai-Hong Wang, Qing-Hua Zhang, Sai-Juan Chen, Qiu-Hua Huang*, Zhu Chen*. Identification and characterization of a novel human histone H3 lysine 36-specific methyltransferase. J Biol Chem 2005 Oct 21;280(42):5261-5271.