PTEN和INK4a/ARF在B细胞发育和造血细胞肿瘤中的重要意义以及急性髓样白血病甲基化基因的研究
|
摘要
抑癌基因的鉴定和功能研究一直以来都是研究的热点。本实验以MB1-Cre-LoxP为基础建立PTEN和(或)INK4a/ARF基因组织特异性敲除模型小鼠共三组。实验发现,PTEN和INK4a/ARF都敲除的模型小鼠肿瘤发生率为100%,肿瘤分为三种:胸腔内、腹腔内和肠道肿瘤,流式细胞仪分析结果显示:各淋巴组织B细胞发育受到影响,主要为Mac-1+,肿瘤细胞具有Mac-1+/B220+,具体为何种造血细胞系肿瘤还需进一步确认。而PTEN或者INK4a/ARF单独缺失的小鼠并未发现类似的肿瘤。对于三组模型小鼠的B细胞发育研究分析表明,单独PTEN缺失组别以及PTEN和INK4a/ARF都缺失的组别在pre-pro-B或更早阶段就已经阻断B细胞发育,而单独INK4a/ARF缺失的模型小鼠B细胞发育没有明显变化。说明PTEN和INK4a/ARF在限制肿瘤生成上具有一定的协同作用,PTEN缺失的小鼠中INK4a/ARF的缺失促进病变进展,其作用机制仍需要深入研究。本论文另一部分重点在于对急性髓样白血病(Acute myeloid leukemia,AML)中甲基化基因的研究,以寻找潜在的抑癌基因。实验通过COBRA和MSP等方法分析研究得到了以ALOX12为代表的一系列潜在抑癌基因。甲基化程度和mRNA表达水平呈负相关,经过去甲基化处理后能恢复表达水平。各潜在抑癌基因的功能分析仍在进行中。
The identification and functional validation of tumor suppressor gene have been a research hotspot. Here, we have established three groups of tissue-specific mouse models of PTEN and (or) INK4a/ARF gene based on MB1-Cre-LoxP model. Tumor incidence in PTEN and INK4a/ARF double knockout mouse was 100%, including tumor in the pleural cavity, abdomen, and tumor linked with intestine. Flow cytometry analysis demonstrated that cells of lymphoid tissues were mainly Mac-1+, and tumor cells were Mac-1 and B220 double positive. The characteristics of this hematopoietic neoplasm still need to be studied. However, mice deficient for either PTEN or INK4a/ARF did not show the occurrence of similar tumors. B cell development was blocked in the pre-pro-B stage or earlier in either PTEN or compound PTEN & INK4a/ARF deficient mice, while there were no such changes in INK4a/ARF null mice. Thus, PTEN and INK4a/ARF show synergy in constraining tumorigenesis. INK4a/ARF deficiency likely facilitates tumor development in PTEN null mice, although the mechanism of which remains undetermined. Additional aspect of this thesis focused on identifying potential tumor suppressors that are methylated in acute myeloid leukemia. Using the method of COBRA and MSP, we have identified a few potential tumor suppressors such as ALOX12. The methylation status around the ALOX12 CpG-island inversely correlated with the expression levels of mRNA. On the other hand, its expression was restored by demethylation reagent such as 5-aza treatment. Further functional studies are undertaken.
The identification and functional validation of tumor suppressor gene have been a research hotspot. Here, we have established three groups of tissue-specific mouse models of PTEN and (or) INK4a/ARF gene based on MB1-Cre-LoxP model. Tumor incidence in PTEN and INK4a/ARF double knockout mouse was 100%, including tumor in the pleural cavity, abdomen, and tumor linked with intestine. Flow cytometry analysis demonstrated that cells of lymphoid tissues were mainly Mac-1+, and tumor cells were Mac-1 and B220 double positive. The characteristics of this hematopoietic neoplasm still need to be studied. However, mice deficient for either PTEN or INK4a/ARF did not show the occurrence of similar tumors. B cell development was blocked in the pre-pro-B stage or earlier in either PTEN or compound PTEN & INK4a/ARF deficient mice, while there were no such changes in INK4a/ARF null mice. Thus, PTEN and INK4a/ARF show synergy in constraining tumorigenesis. INK4a/ARF deficiency likely facilitates tumor development in PTEN null mice, although the mechanism of which remains undetermined. Additional aspect of this thesis focused on identifying potential tumor suppressors that are methylated in acute myeloid leukemia. Using the method of COBRA and MSP, we have identified a few potential tumor suppressors such as ALOX12. The methylation status around the ALOX12 CpG-island inversely correlated with the expression levels of mRNA. On the other hand, its expression was restored by demethylation reagent such as 5-aza treatment. Further functional studies are undertaken.
引文
[1] Li D. M., Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997, 57 (11): 2l24-2l29.
[2] Steck P. A., Pershouse M. A., Jasser S. A. Identification of a candidate tumour suppressor gene, MMAC-1, at chromosome 10q23.3 that is mutated in multiple advanced can. Nat Genet, 1997, 15(4): 356-362.
[3] Li J., Yen C., Liaw D., et a1. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science, 1997, 275(5308): 1943-1947.
[4]韩杨,程克棣。抑癌基因PTEN的研究进展。国外医学药学分册,2006,33(4): 241-245.
[5] Georgescu M. M., Kirsch K. H., Kaloudis P., et al. Stabilization and productive positioning roles of the C2 domain of PIEN tutnor suppressor [J]. Cancer Res, 2000, 60(24): 7033-7038.
[6] Vazquez F., Ramaswamy S., Nakamura N., el al. Phosphorylation of the PIEN tail regulates protein stability and function[J]. Mol Cell Biol, 2000, 20(14): 5010-5018.
[7] Das S., Dixon J. E., Cho W. Membrane-binding and activation mechanism of PTEN [J]. Proc Natl Acad Sci, USA, 2003, 1170(13): 7491-7496.
[8] Li J., Simpson L., Takahashi M., et al. The PTEN/MMAC-1 Tumor Suppressor Induces Cell Death That Is Rescued by the AKT/Protein Kinase B Oncogene. Cancer Res, 1998, 58(24): 5667-5672.
[9] Tamura M., Gu J., Matsomoto K., et al. Inhibilation of cell migration,spreading and focal adhensions by tumor suppressor PTEN[J]. Science, 1998, 280: 1614-1617.
[10]张伟峰。PTEN基因的研究进展。国外医学外科学分册,2003, 30(5): 294-296.
[11]罗彬,云翔。抑癌基因PTEN在胃癌中的研究进展。广东医学, 2006,27(10) 1574-1576.
[12] Salmena L., Carracedo A., Pandolfi P. P. Tenets of PTEN tumor suppression. Cell, 2008, 133:403-414.
[13] Liu J. L., Mao Z., LaFortune T. A., Alonso M. M., Gallick G. E., Fueyo J., Yung W. K. Cell cycle-dependent nuclear export of phosphatase and tensin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade. Cancer Res, 2007, 67, 11054-11063.
[14] Trotman L. C., Wang X., Alimonti A., Chen Z., Teruya-Feldstein J., Yang H., Pavletich N. P., Carver B. S., Cordon-Cardo C., Erdjument-Bromage H., et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell, 2007, 28, 141-156.
[15] Chung, J.-H., Ginn-Pease, M.E., and Eng, C. (2005). Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has nuclear localization signallike sequences for nuclear import mediated bymajor vault protein. Cancer Res. 65, 4108–4116.
[16] Minaguchi T., Waite K. A., Eng C. Nuclear localization of PTEN is regulated by Ca2+ through a tyrosil phosphorylation-independent conformational modification in major vault protein. Cancer Res, 2007, 66, 11677-11682.
[17] Liu F., Wagner S., Campbell R. B., Nickerson, J. A., Schiffer C.A., Ross A. H. PTEN enters the nucleus by diffusion. Cell Biochem, 2005, 96, 221-234.
[18] Gil A., Andres-Pons A., Fernandez E., Valiente M., Torres J., Cervera J., Pulido R. Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs. Mol Biol Cell, 2006, 17, 4002-4013.
[19] Maehama T., Taylor G. S., Dixon J. E. PTEN and myotubularin: Novel phosphoinositide phosphatases. Annu Rev Biochem. 2001, 70, 247-279 .
[20] Ali I. U., Schriml L. M., Dean M., Mutational spectra of PTEN/MMAC-1 gene: A tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst. 1999, 91, 1922-1932.
[21] Maehama T., Dixon J. E., The tumor suppressor, PTEN/MMAC-1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998, 273, 13375-13378.
[22] Myers M. P., Pass I., Batty I. H., Van der Kaay J., Stolarov J. P., Hemmings B. A., Wigler M. H., Downes C. P., Tonks N. K. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci, U.S.A. 1998, 95, 13513-13518.
[23] Han S. Y., Kato H., Kato S., Suzuki T., Shibata H., Ishii S., Shiiba K., Matsuno S., Kanamaru R., Ishioka C. Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. Cancer Res. 2000, 60, 3147-3151.
[24] Furnari F. B., Huang H. J., Cavenee W. K. The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res, 1998, 58, 5002-5008.
[25] Myers M. P., Stolarov J. P., Eng C., Li J., Wang S. I., Wigler M. H., Parsons R., Tonks N. K. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci,U.S.A., 1997, 94, 9052-9057.
[26] Koul D., Jasser S. A., Lu Y., Davies M. A., Shen R., Shi Y., Mills G. B., Yung W. K. Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity. Oncogene, 2002, 21, 2357-2364.
[27] SanoT., Lin H., Chen X., et al. Differential expression of MMAC/PTEN in glioblastoma multiforme: Relationship to localization and prognosis. Cancer Res, 1999, 59(8): 1820-1824.
[28] Sansal I., Sellers W. R. The biology and clinical relevance of the PTEN tumor suppressor pathway. JClin Oncol, 2004,22:2954-2963.
[29] Li L., Alonzo H., Ross. Why Is PTEN an Important Tumor Suppressor? Journal of Cellular Biochemistry, 2007, 102: 1368-1374.
[30] Veloso M., Wrba F., Kaserer K., et al. p53 gene status and expression of p53, mdm2, and p21 Waf1/Cipl proteins in colorectal cancer[J]. Virchows Arch, 2000, 437(3): 241.
[31] Quelle D. E., Zindy F., Ashmun R. A., et al. Alternative reading frames of the INK4a tumor suppressor gene encode tow unrelated proteins capable of inducing cell cycle arrest[J]. Cell, 1995, 83:993.
[32] Serrano M. A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/CDK4[J]. Nature,1993, 366(6456 ): 704.
[33] Duro D., Bernard O., Della Valle V., et al. A new type of p16INK4/MTS1 gene transcript expressed in B cell malignancies [J]. Oncogene, 1995, 11(1): 21-29.
[34] Mao L., Merlo A., Bedi G., et al. A novel p16INK4a transcript [J]. Cancer Res, 1995, 55 (14):2995-2997.
[35] Quelle D. E., Zindy F., Ashmun R. A., et al. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest [J]. Cell, 1995, 83(6):993-1000.
[36] Haber D. A. Splicing into senescence: the curious case of p16 and p19 ARF[J]. C ell, 1997, 91:5.
[37] Justin H. Berger and Nabeel Bardeesy. Modeling INK4/ARF Tumor Suppression in the Mouse [J]. Current Molecular Medicine, 2007, 7, 63-75.
[38]胡义德,高楠,曹世龙。肺癌INK4和ARF基因缺失与突变研究进展[J],国外医学·呼吸系统分册,2000,20(2):102-104.
[39] Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q.,Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. Science, 1994, 264, 436-440.
[40] Hussussian C. J., Struewing J. P., Goldstein A. M., Higgins P.A., Ally D. S., Sheahan M. D., Clark W. H., Jr., Tucker M. A., Dracopoli N. C. Nat Genet, 1994, 8, 15-21.
[41] Goldstein A. M., Fraser M. C., Struewing J. P., Hussussian C.J., Ranade K., Zametkin D.P., Fontaine L. S., Organic S. M., Dracopoli N. C., Clark W. H., Jr. and Tucker M.A. N Engl J Med, 1995, 333, 970-974.
[42] Sherr C. J., McCormick F. The RB and p53 pathways in cancer. Cancer Cell, 2002, 2, 103-112.
[43] CBTRUS (2005). Statistical Report: Primary Brain Tumors in the United States, 1998-2002. Published by the Central Brain Tumor Registry of the United States.
[44] Ries L. A. G., Harkins D., Krapcho M., Mariotto A., Miller B. A., Feuer E. J., Clegg L., Eisner M. P., Horner M. J., Howlader N., Hayat M., Hankey B. F., Edwards B. K. (eds). SEER Cancer Statistics Review, 1975-2003, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2003/, based on November 2005 SEER data submission, posted to the SEER web site, 2006.
[45] Merlo A., Herman J. G., Mao L., Lee D. J., Gabrielson E., Burger P. C., Baylin S. B., Sidransky D. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Nat Med, 1995,1, 686-692.
[46] Otterson G. A., Kratzke R. A., Coxon A., Kim Y. W., Kaye F. J. Absence of p16(INK4) protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene, 1994, 9, 3375-3378.
[47] Shapiro G. I., Edwards C. D., Kobzik L., Godleski J., Richards W., Sugarbaker D. J., Rollins B. Reciprocal Rb inactivation and p16(INK4) expression in primary lung cancers and cell lines. J Cancer Res, 1995, 55, 505-509.
[48] Jarrard D. F., Bova G. S., Ewing C. M., Pin S. S., Nguyen S. H., Baylin S. B., Cairns P., Sidransky D., Herman J. G., Isaacs W. B. Deletional, mutational, and methylation analyses of CDKN2 (pI6/MTSI) in primary and merastatic prostate cancer. Genes Chromosomes Cancer, 1997, 19, 90-96.
[49] Chen W., Weghorst C. M., Sabourin C. L., Wang Y., Wang D., Bostwick D. G., Stoner G. D. Absence of p16/MTS1 gene mutations in human prostate cancer. Carcinogenesis, 1996, 17, 2603-2607.
[50] Kozar K., Ciemerych M. A., Rebel V. I., Shigematsu H., Zagozdzon A., Sicinska E., Geng Y., Yu, Q., Bhattacharya S., Bronson R. T., Akashi K., Sicinski P. Mouse development and cell proliferation in the absence of D-cyclins. Cell, 2004, 118, 477-491.
[51] Deshpande A., Sicinski P., Hinds P. W. Cyclins and cdks in development and cancer: A perspective. Oncogene, 2005, 24, 2909-2915.
[52] Herman J. G., Graff J. R., Myohanen S., Nelkin B. D., Baylin S. B. Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci, USA, 1996, 93, 9821-9826.
[53] Batova A., Diccianni M. B., Yu J. C., Nobori T., Link M. P., Pullen J., Yu A. L. Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia. Cancer Res, 1997, 57, 832-836.
[54] Ng M. H., Chung Y. F., Lo K. W., Wickham N. W., Lee J. C., Huang D. P. Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood, 1997, 89, 2500-2506.
[55] Wilentz R. E., Geradts J., Maynard R., Offerhaus G. J., Kang M., Goggins M., Yeo C. J., Kern S. E., Hruban R. H. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: Loss of intranuclear expression. Cancer Res, 1998, 58, 4740-4744.
[56] Moskaluk C. A., Hruban R. H., Kern S. E. Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma. Cancer Res, 1997, 57, 2140-2143.
[57] Wang H., Presland R. B., Piepkorn M. A search for CDKN2A/p16INK4a mutations in melanocytic nevi from patients with melanoma and spouse controls by use of laser-captured microdissection. Arch Dermatol, 2005, 141, 177-180.
[58] Nielsen G. P., Stemmer-Rachamimov A. O., Shaw J., Roy J. E., Koh J., Louis D. N. Immunohistochemical survey of p16(INK4A) expression in normal human adult and infant tissues. Lab Invest, 1999, 79, 1137-1143.
[59] Krishnamurthy J., Torrice C., Ramsey M. R., Kovalev G. I., Al-Regaiey K., Su L., Sharpless N. E. Ink4a/Arf expression is a biomarker of aging. J Clin Invest, 2004, 114, 1299-1307.
[60] Natarajan E., Saeb M., Crum C. P., Woo S. B., McKee P. H., Rheinwald J. G. Co-expression of p16INK4A and laminin 5γ2 by microinvasive and superficial squamous cell carcinomas in vivo and by migrating wound and senescent keratinocytes in culture. Am J Pathol, 2003, 163, 477-491.
[61] Michaloglou C., Vredeveld L. C., Soengas M. S., Denoyelle C., Kuilman T., van der Horst C. M., Majoor D. M., Shay J. W., Mooi W. J., Peeper D. S. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature, 2005, 436, 720-724.
[62] Braig M., Lee S., Loddenkemper C., Rudolph C., Peters A. H., Schlegelberger B., Stein H., Dorken B., Jenuwein T., Schmitt C. A. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature, 2005, 436, 660-665.
[63] Collado M., Gil J., Efeyan A., Guerra C., Schuhmacher A. J., Barradas M., Benguria A., Zaballos A., Flores J. M., Barbacid M., Beach D., Serrano M. Tumour biology: Senescence in premalignant tumours. Nature, 2005, 436, 642.
[64] Chen Z., Trotman L. C., Shaffer D., Lin H. K., Dotan Z. A., Niki M., Koutcher J. A., Scher H. I., Ludwig T., Gerald W., Cordon-Cardo C., Pandolfi P. P. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature, 2005, 436, 725-730.
[65] Sharpless N. E., DePinho R. A. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev, 1999, 9, 22-30.
[66] Rizos H., Puig S., Badenas C., Malvehy J., Darmanian A. P., Jimenez L., Mila M., Kefford R. F. A melanoma-associated germline mutation in exon 1βinactivates p14ARF. Oncogene, 2001, 20, 5543-5547.
[67] Randerson-Moor J. A., Harland M., Williams S., Cuthbert-Heavens D., Sheridan E., Aveyard J., Sibley K., Whitaker L., Knowles M., Newton Bishop J., Bishop D. T. A germline deletion of p14ARF but notCDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet, 2001, 10, 55-62.
[68] Hewitt C., Lee Wu C., Evans G., Howell A., Elles R. G., Jordan R., Sloan P., Read A. P., Thakker, N. Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Hum Mol Genet, 2002, 11, 1273-1279.
[69] Kwong R. A., Kalish L. H., Nguyen T. V., Kench J. G., Bova R. J., Cole I. E., Musgrove E. A., Sutherland R. L. p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue. Clin Cancer Res, 2005, 11, 4107-4116.
[70] Esteller M., Gonzalez S., Risques R. A., Marcuello E., Mangues R., Germa J. R., Herman J. G., Capella G., Peinado M. A. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol, 2001, 19, 299-304.
[71] Esteller M., Tortola S., Toyota M., Capella G., Peinado M. A., Baylin S. B., Herman J. G. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res, 2000, 60, 129-133.
[72] Sato F., Harpaz N., Shibata D., Xu Y., Yin J., Mori Y., Zou T. T., Wang S., Desai K., Leytin A., Selaru F. M., Abraham J. M., Meltzer S. J. Hypermethylation of the p14ARF gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res, 2002, 62, 1148-1151.
[73] Burri N., Shaw P., Bouzourene H., Sordat I., Sordat B., Gillet M., Schorderet D., Bosman F. T., Chaubert P. Methylation silencing and mutations of the p14ARF and p16INK4a genes in colon cancer. Lab Invest, 2001, 81, 217-229.
[74]赵茜,陆融。磷脂酰肌醇3激酶-蛋白质丝氨酸苏氨酸激酶途径与肿瘤的关系国际肿瘤学杂志。2006,33(6):401-404.
[75] Ward S. G., Finan P. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr Opin Pharmacol, 2003, 3: 426-434.
[76] Solit D. B., Basso A. D., Olshen A. B., Scher H. I., Rosen N. Inhibition of heat shock protein 90 function downregulates Akt kinase and sensitizes tumors to Taxol. Cancer Res, 2003, 63: 2139-2144.
[77]孙晓杰,黄常志。PI3K-Akt信号通路与肿瘤世界华人消化杂志。2006,14(3): 306-311.
[78] Katso R., Okkenhaug K., Ahmadi K., White S., Timms J., Waterfield M. D. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol, 2001, 17: 615-675.
[79] Maehama T., Taylor G. S., Dixon J. E. PTEN and myotubularin: Novel phosphoinositide phosphatases. Annu Rev Biochem, 2001, 70, 247-279.
[80] Maehama T., Dixon J. E., The tumor suppressor, PTEN/MMAC-1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. Biol Chem, 1998, 273, 13375-13378.
[81] Myers M. P., Pass I., Batty I. H., Van der Kaay J., Stolarov J. P., Hemmings B. A., Wigler M. H., Downes C. P., Tonks N. K. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci, U.S.A., 1998, 95, 13513-13518 .
[82] Cantley L. C., Neel B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U.S.A., 1999, 96, 4240-4245.
[83] Franca-Koh J., Kamimura Y., Devreotes P. N. Leading-edge research: PtdIns(3,4,5)P3 and directed migration. Nat Cell Biol, 2007, 9, 15-17.
[84] Rossi D. J., Weissman I. L. Pten, Tumorigenesis, and Stem Cell Self-Renewal. Cell, 2006, 125, 229-231.
[85] Leslie N. R., Downes C. P. PTEN function: How normal cells control it and tumour cells lose it. Biochem J. 2004,382, 1-11.
[86] Sulis M. L., Parsons R. PTEN: From pathology to biology. Trends Cell Biol, 2003, 13, 478-483.
[87] Vazquez F., Sellers W. R. The PTEN tumor suppressor protein: An antagonist of phosphoinositide 3- kinase signaling. Biochim Biophys Acta, 2000, 1470, M21-35.
[88] Di Cristofano A., Pandolfi P. P. The multiple roles of PTEN in tumor suppression. Cell, 2000,100, 387-390.
[89] Lowe S. W., Sherr C. J. Tumor suppression by Ink4a-Arf: Progress and puzzles Curr Opin Genet Dev, 2003, 13, 77-83.
[90] Sherr C. J., McCormick F. The RB and p53 pathways in cancer. Cancer Cell, 2002, 2, 103-112.
[91] Pomerantz J., Schreiber-Agus N., Liegeois N. J., Silverman,A., Alland L., Chin L., Potes J., Chen K., Orlow I., Lee H. W., Cordon-Cardo C., DePinho R. A. The Ink4a tumor suppressor gene product, p19(Arf), interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell, 1998, 92, 713-723.
[92] Zhang Y., Xiong Y., Yarbrough W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell, 1998, 92, 725-734.
[93] Kamijo T., Weber J. D., Zambetti G., Zindy F., Roussel M. F., Sherr C. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci, USA, 1998, 95, 8292-8297.
[94] Stott F. J., Bates S., James M. C., McConnell B. B., Starborg M., Brookes S., Palmero I., Ryan K.,Hara E., Vousden K. H., Peters, G. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J, 1998, 17, 5001-5014.
[95] Radfar A., Unnikrishnan I., Lee H. W., DePinho R. A., Rosenberg N. p19Arf induces p53-dependent apoptosis during Abelson virus-mediated pre-B cell transformation. Proc Natl Acad Sci, USA, 1998,95, 13194-13199.
[96] Zindy F., Eischen C. M., Randle D. H., Kamijo T., Cleveland J. L., Sherr C. J., Roussel M. F. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev, 1998, 12, 2424-2433.
[97] de Stanchina E., McCurrach M. E., Zindy F., Shieh S. Y., Ferbeyre G., Samuelson A. V., Prives C., Roussel M. F., Sherr C. J., Lowe S. W. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev, 1998, 12, 2434-2442.
[98] Bates S., Phillips A. C., Clark P. A., Stott F., Peters G., Ludwig R. L., Vousden K. H. p14(ARF) links the tumour suppressors RB and p53 [5]. Nature, 1998, 395, 124-125.
[99] Sharpless N. E., Ramsey M. R., Balasubramanian P., Castrillon D. H., DePinho R. A. The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. Oncogene, 2004, 23, 379-385.
[100]卞寿庚。白血病[M]。中国医药科技出版社。2003
[101]仇霞芬。白血病[M]。中国医药科技出版社。2009
[102]宋善俊,陆道培,郝玉书(医学)。白血病[M]。湖北科学技术出版社。2004.
[103]刘新月。新编白血病细胞形态诊断学[M]。华中科技大学出版社。2008
[104] Jemal A., Thomas A., Murray T., Thun M. Cancer statistics 2002. CA Cancer J Clin 52:23, 2002.
[105]王亚平。造血干细胞生物学及其研究方法[M]。科学出版社。2007
[106] Orkin S. H., Zon LI. Snapshot: Hematopoiesis. Cell, 2008, 132.
[107] Tucker W. LeBien, Thomas F., Tedder B. lymphocytes: how they develop and function. Blood, 2008, 112(5), 1570-1580.
[108] Stephen L., Nutt, Barbara L., Kee. The Transcriptional Regulation of B Cell Lineage Commitment. DOI 10.1016/j.immuni.2007, 05, 010.
[109] Nutt S. L., Kee B. L. The transcriptional regulation of B cell lineage commitment. Immunity. 2007, 26, 715-725.
[110] Scott E.W., Simon M.C., Anastasi J., Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science, 1994, 265, 1573–1577.
[111] Bain G., et al. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell, 1994,79, 885-892.
[112] Lin H., Grosschedl R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature, 1995,376, 263-267.
[113] Seet C. S., Brumbaugh R. L., Kee B. L. Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. J Exp Med, 2004, 199, 1689-1700.
[114] Johnson K., et al. Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. Immunity. 2008, 28, 335-345.
[115] Richard R., Hardy, Paul W., Kincade, Kenneth Dorshkind. The Protean Nature of Cells in the B Lymphocyte Lineage. Immunity, 2007, 703-714.
[116] Klausner R.D. Studying cancer in the mouse. Oncogene, 1999, 18(38): 5249-5252.
[117] Desjatlais Jr,Berg JM Protein,1992,13:272
[118] Akira Suzuki, Tsuneyasu Kaisho, Minako Ohishi, et al. Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination[J]. J Exp Med, 2003, (197) 657-667.
[119] Suzuki A., de la Pompa J. L., Stambolic V., Elia A.J., Sasaki T., del Barco Barrantes I., Ho A., Wakeham A., Itie A., Khoo W., et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol, 1998, 8:1169-1178.
[120] Stambolic V., Suzuki A., de la Pompa J.L., Brothers G.M., Mirtsos C., Sasaki T., Ruland J., Penninger J.M., Siderovski D.P., Mak T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998, 95:29-39.
[121] Stambolic V., Tsao M.S., Macpherson D., Suzuki A., W.B. Chapman, Mak T.W. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten_/_ mice. Cancer Res. 2000, 60:3605–3611.
[122] Podsypanina K., Ellenson L.H., Nemes A., Gu J., Tamura M., Yamada K.M., Cordon-Cardo C., Catoretti G., Fisher P.E., Parsons R. Mutation of Pten/MMac-1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci, USA, 1999, 96:1563-568.
[123] Di Cristofano, A., Kotsi P., Peng Y.F., Cordon-Cardo C., Elkon K.B., Pandolfi P.P. Impaired Fas response and autoimmunity in Pten_/_ mice. Science, 1999, 285:2122–2125.
[124] Suzuki A., Yamaguchi M.T., Ohteki T., Sasaki T., Kaisho T., Kimura Y., Yoshida R., Wakeham A., Higuchi T., Fukumoto M., et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity, 2001, 14:523-534.
[125] Gronbaek K., Zeuthen J., Guldberg P., Ralfkiaer E., Hou-Jensen K. Alterations of the MMAC-1/PTEN gene in lymphoid malignancies. Blood, 1998, 91:4388-4390.
[126] Nakahara Y., Nagai H., Kinoshita T., Uchida T., Hatano S., Murate T., Saito H. Mutational analysis of the PTEN/MMAC-1 gene in non-Hodgkin’s lymphoma. Leukemia, 1998, 12:1277-1280.
[127] Hyun T., Yam A., Pece S., Xie X., Zhang J., Miki T., Gutkind J.S., Li W. Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood, 2000, 96:3560-3568.
[128] Zheng H., Ying H., Yan H., et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature, 2008, 455(7216): 1129-1133.
[129] Ralf Lesche, Matthias Groszer, Jing Gao, Ying Wang, Albee Messing, Hong Sun, Xin Liu, Hong Wu. Cre/loxP-Mediated Inactivation of the Murine Pten Tumor Suppressor Gene. Genesis, 2002,32:148-149.
[130] Zhuo L., Theis M., Alvarez-Maya I., Brenner M., Willecke K., Messing A. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis, 2001, 31(2):85-94.
[131] Berger J. H., Bardeesy N. Modeling INK4/ARF Tumor Suppression in the Mouse. Current Molecular Medicine, 2007, 7, 63-75.
[132] Sharpless N. E., Bardeesy N., Lee K. H., Carrasco D., Castrillon D. H., Aguirre A. J., Wu E. A., Horner J. W., DePinho R. A. Loss of p16Ink4a with retention of p19 predisposes mice to tumorigenesis. Nature, 2001, 413, 86-91.
[133] Krimpenfort P., Quon K. C., Mooi W. J., Loonstra A., Berns A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature, 2001, 413, 83-86.
[134] Kamijo T., Zindy F., Roussel M. F., Quelle D. E., Downing J. R., Ashmun R. A., Grosveld G., Sherr C. J. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19(ARF). Cell, 1997, 91, 649-659.
[135] Sharpless N. E., Ramsey M. R., Balasubramanian P., Castrillon D. H., DePinho, R. A. () Oncogene, 2004, 23, 379-385
[136] Serrano M., Lee H., Chin L., Cordon-Cardo C., Beach D., DePinho, R. A. The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. Cell, 1996, 85, 27-37.
[137] Haluska F. G., Tsao H., Wu H., Haluska F. S., Lazar A., Goel V. Genetic alterations in signaling pathways in melanoma Clin Cancer Res, 2006, 12, 2301s-2307s.
[138] Maher E. A., Furnari F. B., Bachoo R. M., Rowitch D. H., Louis D. N., Cavenee W. K., DePinho R. A. Malignant glioma: Genetics and biology of a grave matter. Genes Dev, 2001, 15, 1311-1333.
[139] Daniotti M., Oggionni M., Ranzani T., Vallacchi V., Campi V., Di Stasi D., Torre G. D., Perrone F.,Luoni C., Suardi S., Frattini M., Pilotti S., Anichini A., Tragni G., Parmiani G., Pierotti M. A., Rodolfo M. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene, 2004, 23, 5968-5977.
[140] Daniel R. Carrasco, Tim Fenton, Kumar Sukhdeo, et al. The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans[J]. Cancer Cell, 2006(9), 379-390.
[141] Hobeika E., Thiemann S., Storch B. Testing gene function early in the B cell lineage in mb1-cre mice. PNAS, 2006, 103(37):13789-13794.
[142] Holliday R. A re-examination of the effects of ionizing radiation on lifespan and transformation of human diploid fibroblasts. Mut Res, 1991, 256 (2-6), pp. 295-302.
[143] Holliday R., Grigg G. W. DNA methylation and mutation. Mut Res,1993, 285:61.
[144] Cheng K. C., Loeb L. A., Genomic instability and tumor progression: Mechanistic considerations. Adv Cancer Res, 1993, 60:121.
[145] Reik W., Dean W., Walter J. Epigenetic reprogramming in mammalian development, Science, 2001, 293: 1089-1093
[146] Baylin S. B., Herman J. G., DNA hyperrnethylation in tumorigenesis: epigenetics joins genetics Trends Cenet, 2000, 16:168-174.
[147] Bender J. Cytosine methylation of repeated sequences in eukaryotes: the role of DNA pairing. Tremh Biochem Sci. 1998, 23: 252-256.
[148] Yoder J. A., Walsh C. P., Bestor T. H. Cytosine methylation and the ecology of intragenomic parasites Trends Cenet. 1997, 13:335-340.
[149]朱卫国。DNA甲基化,基因调控和癌症。世界华人消化杂志。2002, 10(6) 680-683.
[150] Kuang S. Q., Tong W. G., Yang H., et al. Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia. Leukemia, 2008, 22, 1529-1538.
[151] Costello J. F., Plass C.J. Aberrant methylation of genes in low-grade astrocytomas. Med Genet, 2001, 38(5): 285-303.
[152] Stirzaker C., Millar D.S., Paul C.L., Warnecke P.M., Harrison J., Vincent P.C., Frommer M., Clark S.J. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Research, 1997, 57 (11), pp. 2229-2237.
[153] Adams R. L. Eukaryotic DNA methyltransferases - Structure and function. Bioessays, 1995, 17(2): 139-145.
[154] Fraga M.F., Rodríguez R., Ca?al M.J. Rapid quantification of DNA methylation by high performance capillary electrophoresis. Electrophoresis, 2000, 21 (14), pp. 2990-2994.
[155] Gonzalgo M.L., Liang G., Spruck III, C.H., Zingg J.-M., Rideout III W.M., Jones P.A. Identification and characterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR1. Cancer Research, 1997, 57 (4), pp. 594-599.
[156] Frommer M., McDonald L. E., Millar D. S., Collis C. M., Watt F., Grigg G. W., Molloy P.L., Paul C.L. A genomic sequencing protocol that yields a positive display of 5- methylcytosine residues in individual DNA strands. Proc Natl Acad Sci, USA, 1992, 89(5): 1827-1831.
[157] Cindy A., Eads, Peter W., Laird. Combined Bisulfite Restriction Analysis (COBRA)[M]. Methods in Molecular Biology, volume 200:DNA Methylation Protocols.
[158] Aude Thiriot,et al. The Bw Cells, a Novel B Cell Population Conserved in the Whole Genus Mus. The Journal of Immunology, 2007, 179: 6568–6578.
[159] Wolfgang Walter, et al. Differential expression of alternative H2-M isoforms in B cells,dendritic cells and macrophages by proin ammatory cytokines[J]. Molecular Immunology 36 (1999) 733±743
[160] S-Q Kuang, W-G Tong, H Yang,et al. Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia[J]. Leukemia (2008) 22, 1529–1538
[161] Goodman, J.E., Bowman, E.D., Chanock, S.J., Alberg, A.J., Harris, C.C. Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk[J]. 2004 Carcinogenesis 25 (12):2467-2472
[2] Steck P. A., Pershouse M. A., Jasser S. A. Identification of a candidate tumour suppressor gene, MMAC-1, at chromosome 10q23.3 that is mutated in multiple advanced can. Nat Genet, 1997, 15(4): 356-362.
[3] Li J., Yen C., Liaw D., et a1. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast and prostate cancer. Science, 1997, 275(5308): 1943-1947.
[4]韩杨,程克棣。抑癌基因PTEN的研究进展。国外医学药学分册,2006,33(4): 241-245.
[5] Georgescu M. M., Kirsch K. H., Kaloudis P., et al. Stabilization and productive positioning roles of the C2 domain of PIEN tutnor suppressor [J]. Cancer Res, 2000, 60(24): 7033-7038.
[6] Vazquez F., Ramaswamy S., Nakamura N., el al. Phosphorylation of the PIEN tail regulates protein stability and function[J]. Mol Cell Biol, 2000, 20(14): 5010-5018.
[7] Das S., Dixon J. E., Cho W. Membrane-binding and activation mechanism of PTEN [J]. Proc Natl Acad Sci, USA, 2003, 1170(13): 7491-7496.
[8] Li J., Simpson L., Takahashi M., et al. The PTEN/MMAC-1 Tumor Suppressor Induces Cell Death That Is Rescued by the AKT/Protein Kinase B Oncogene. Cancer Res, 1998, 58(24): 5667-5672.
[9] Tamura M., Gu J., Matsomoto K., et al. Inhibilation of cell migration,spreading and focal adhensions by tumor suppressor PTEN[J]. Science, 1998, 280: 1614-1617.
[10]张伟峰。PTEN基因的研究进展。国外医学外科学分册,2003, 30(5): 294-296.
[11]罗彬,云翔。抑癌基因PTEN在胃癌中的研究进展。广东医学, 2006,27(10) 1574-1576.
[12] Salmena L., Carracedo A., Pandolfi P. P. Tenets of PTEN tumor suppression. Cell, 2008, 133:403-414.
[13] Liu J. L., Mao Z., LaFortune T. A., Alonso M. M., Gallick G. E., Fueyo J., Yung W. K. Cell cycle-dependent nuclear export of phosphatase and tensin homologue tumor suppressor is regulated by the phosphoinositide-3-kinase signaling cascade. Cancer Res, 2007, 67, 11054-11063.
[14] Trotman L. C., Wang X., Alimonti A., Chen Z., Teruya-Feldstein J., Yang H., Pavletich N. P., Carver B. S., Cordon-Cardo C., Erdjument-Bromage H., et al. Ubiquitination regulates PTEN nuclear import and tumor suppression. Cell, 2007, 28, 141-156.
[15] Chung, J.-H., Ginn-Pease, M.E., and Eng, C. (2005). Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) has nuclear localization signallike sequences for nuclear import mediated bymajor vault protein. Cancer Res. 65, 4108–4116.
[16] Minaguchi T., Waite K. A., Eng C. Nuclear localization of PTEN is regulated by Ca2+ through a tyrosil phosphorylation-independent conformational modification in major vault protein. Cancer Res, 2007, 66, 11677-11682.
[17] Liu F., Wagner S., Campbell R. B., Nickerson, J. A., Schiffer C.A., Ross A. H. PTEN enters the nucleus by diffusion. Cell Biochem, 2005, 96, 221-234.
[18] Gil A., Andres-Pons A., Fernandez E., Valiente M., Torres J., Cervera J., Pulido R. Nuclear localization of PTEN by a Ran-dependent mechanism enhances apoptosis: involvement of an N-terminal nuclear localization domain and multiple nuclear exclusion motifs. Mol Biol Cell, 2006, 17, 4002-4013.
[19] Maehama T., Taylor G. S., Dixon J. E. PTEN and myotubularin: Novel phosphoinositide phosphatases. Annu Rev Biochem. 2001, 70, 247-279 .
[20] Ali I. U., Schriml L. M., Dean M., Mutational spectra of PTEN/MMAC-1 gene: A tumor suppressor with lipid phosphatase activity. J Natl Cancer Inst. 1999, 91, 1922-1932.
[21] Maehama T., Dixon J. E., The tumor suppressor, PTEN/MMAC-1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998, 273, 13375-13378.
[22] Myers M. P., Pass I., Batty I. H., Van der Kaay J., Stolarov J. P., Hemmings B. A., Wigler M. H., Downes C. P., Tonks N. K. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci, U.S.A. 1998, 95, 13513-13518.
[23] Han S. Y., Kato H., Kato S., Suzuki T., Shibata H., Ishii S., Shiiba K., Matsuno S., Kanamaru R., Ishioka C. Functional evaluation of PTEN missense mutations using in vitro phosphoinositide phosphatase assay. Cancer Res. 2000, 60, 3147-3151.
[24] Furnari F. B., Huang H. J., Cavenee W. K. The phosphoinositol phosphatase activity of PTEN mediates a serum-sensitive G1 growth arrest in glioma cells. Cancer Res, 1998, 58, 5002-5008.
[25] Myers M. P., Stolarov J. P., Eng C., Li J., Wang S. I., Wigler M. H., Parsons R., Tonks N. K. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci,U.S.A., 1997, 94, 9052-9057.
[26] Koul D., Jasser S. A., Lu Y., Davies M. A., Shen R., Shi Y., Mills G. B., Yung W. K. Motif analysis of the tumor suppressor gene MMAC/PTEN identifies tyrosines critical for tumor suppression and lipid phosphatase activity. Oncogene, 2002, 21, 2357-2364.
[27] SanoT., Lin H., Chen X., et al. Differential expression of MMAC/PTEN in glioblastoma multiforme: Relationship to localization and prognosis. Cancer Res, 1999, 59(8): 1820-1824.
[28] Sansal I., Sellers W. R. The biology and clinical relevance of the PTEN tumor suppressor pathway. JClin Oncol, 2004,22:2954-2963.
[29] Li L., Alonzo H., Ross. Why Is PTEN an Important Tumor Suppressor? Journal of Cellular Biochemistry, 2007, 102: 1368-1374.
[30] Veloso M., Wrba F., Kaserer K., et al. p53 gene status and expression of p53, mdm2, and p21 Waf1/Cipl proteins in colorectal cancer[J]. Virchows Arch, 2000, 437(3): 241.
[31] Quelle D. E., Zindy F., Ashmun R. A., et al. Alternative reading frames of the INK4a tumor suppressor gene encode tow unrelated proteins capable of inducing cell cycle arrest[J]. Cell, 1995, 83:993.
[32] Serrano M. A new regulatory motif in cell cycle control causing specific inhibition of cyclin D/CDK4[J]. Nature,1993, 366(6456 ): 704.
[33] Duro D., Bernard O., Della Valle V., et al. A new type of p16INK4/MTS1 gene transcript expressed in B cell malignancies [J]. Oncogene, 1995, 11(1): 21-29.
[34] Mao L., Merlo A., Bedi G., et al. A novel p16INK4a transcript [J]. Cancer Res, 1995, 55 (14):2995-2997.
[35] Quelle D. E., Zindy F., Ashmun R. A., et al. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest [J]. Cell, 1995, 83(6):993-1000.
[36] Haber D. A. Splicing into senescence: the curious case of p16 and p19 ARF[J]. C ell, 1997, 91:5.
[37] Justin H. Berger and Nabeel Bardeesy. Modeling INK4/ARF Tumor Suppression in the Mouse [J]. Current Molecular Medicine, 2007, 7, 63-75.
[38]胡义德,高楠,曹世龙。肺癌INK4和ARF基因缺失与突变研究进展[J],国外医学·呼吸系统分册,2000,20(2):102-104.
[39] Kamb A., Gruis N. A., Weaver-Feldhaus J., Liu Q.,Harshman K., Tavtigian S. V., Stockert E., Day R. S., 3rd, Johnson B. E., Skolnick M. H. Science, 1994, 264, 436-440.
[40] Hussussian C. J., Struewing J. P., Goldstein A. M., Higgins P.A., Ally D. S., Sheahan M. D., Clark W. H., Jr., Tucker M. A., Dracopoli N. C. Nat Genet, 1994, 8, 15-21.
[41] Goldstein A. M., Fraser M. C., Struewing J. P., Hussussian C.J., Ranade K., Zametkin D.P., Fontaine L. S., Organic S. M., Dracopoli N. C., Clark W. H., Jr. and Tucker M.A. N Engl J Med, 1995, 333, 970-974.
[42] Sherr C. J., McCormick F. The RB and p53 pathways in cancer. Cancer Cell, 2002, 2, 103-112.
[43] CBTRUS (2005). Statistical Report: Primary Brain Tumors in the United States, 1998-2002. Published by the Central Brain Tumor Registry of the United States.
[44] Ries L. A. G., Harkins D., Krapcho M., Mariotto A., Miller B. A., Feuer E. J., Clegg L., Eisner M. P., Horner M. J., Howlader N., Hayat M., Hankey B. F., Edwards B. K. (eds). SEER Cancer Statistics Review, 1975-2003, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2003/, based on November 2005 SEER data submission, posted to the SEER web site, 2006.
[45] Merlo A., Herman J. G., Mao L., Lee D. J., Gabrielson E., Burger P. C., Baylin S. B., Sidransky D. Inactivation of the CDKN2/p16/MTS1 gene is frequently associated with aberrant DNA methylation in all common human cancers. Nat Med, 1995,1, 686-692.
[46] Otterson G. A., Kratzke R. A., Coxon A., Kim Y. W., Kaye F. J. Absence of p16(INK4) protein is restricted to the subset of lung cancer lines that retains wildtype RB. Oncogene, 1994, 9, 3375-3378.
[47] Shapiro G. I., Edwards C. D., Kobzik L., Godleski J., Richards W., Sugarbaker D. J., Rollins B. Reciprocal Rb inactivation and p16(INK4) expression in primary lung cancers and cell lines. J Cancer Res, 1995, 55, 505-509.
[48] Jarrard D. F., Bova G. S., Ewing C. M., Pin S. S., Nguyen S. H., Baylin S. B., Cairns P., Sidransky D., Herman J. G., Isaacs W. B. Deletional, mutational, and methylation analyses of CDKN2 (pI6/MTSI) in primary and merastatic prostate cancer. Genes Chromosomes Cancer, 1997, 19, 90-96.
[49] Chen W., Weghorst C. M., Sabourin C. L., Wang Y., Wang D., Bostwick D. G., Stoner G. D. Absence of p16/MTS1 gene mutations in human prostate cancer. Carcinogenesis, 1996, 17, 2603-2607.
[50] Kozar K., Ciemerych M. A., Rebel V. I., Shigematsu H., Zagozdzon A., Sicinska E., Geng Y., Yu, Q., Bhattacharya S., Bronson R. T., Akashi K., Sicinski P. Mouse development and cell proliferation in the absence of D-cyclins. Cell, 2004, 118, 477-491.
[51] Deshpande A., Sicinski P., Hinds P. W. Cyclins and cdks in development and cancer: A perspective. Oncogene, 2005, 24, 2909-2915.
[52] Herman J. G., Graff J. R., Myohanen S., Nelkin B. D., Baylin S. B. Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci, USA, 1996, 93, 9821-9826.
[53] Batova A., Diccianni M. B., Yu J. C., Nobori T., Link M. P., Pullen J., Yu A. L. Frequent and selective methylation of p15 and deletion of both p15 and p16 in T-cell acute lymphoblastic leukemia. Cancer Res, 1997, 57, 832-836.
[54] Ng M. H., Chung Y. F., Lo K. W., Wickham N. W., Lee J. C., Huang D. P. Frequent hypermethylation of p16 and p15 genes in multiple myeloma. Blood, 1997, 89, 2500-2506.
[55] Wilentz R. E., Geradts J., Maynard R., Offerhaus G. J., Kang M., Goggins M., Yeo C. J., Kern S. E., Hruban R. H. Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: Loss of intranuclear expression. Cancer Res, 1998, 58, 4740-4744.
[56] Moskaluk C. A., Hruban R. H., Kern S. E. Genomic sequencing of DPC4 in the analysis of familial pancreatic carcinoma. Cancer Res, 1997, 57, 2140-2143.
[57] Wang H., Presland R. B., Piepkorn M. A search for CDKN2A/p16INK4a mutations in melanocytic nevi from patients with melanoma and spouse controls by use of laser-captured microdissection. Arch Dermatol, 2005, 141, 177-180.
[58] Nielsen G. P., Stemmer-Rachamimov A. O., Shaw J., Roy J. E., Koh J., Louis D. N. Immunohistochemical survey of p16(INK4A) expression in normal human adult and infant tissues. Lab Invest, 1999, 79, 1137-1143.
[59] Krishnamurthy J., Torrice C., Ramsey M. R., Kovalev G. I., Al-Regaiey K., Su L., Sharpless N. E. Ink4a/Arf expression is a biomarker of aging. J Clin Invest, 2004, 114, 1299-1307.
[60] Natarajan E., Saeb M., Crum C. P., Woo S. B., McKee P. H., Rheinwald J. G. Co-expression of p16INK4A and laminin 5γ2 by microinvasive and superficial squamous cell carcinomas in vivo and by migrating wound and senescent keratinocytes in culture. Am J Pathol, 2003, 163, 477-491.
[61] Michaloglou C., Vredeveld L. C., Soengas M. S., Denoyelle C., Kuilman T., van der Horst C. M., Majoor D. M., Shay J. W., Mooi W. J., Peeper D. S. BRAFE600-associated senescence-like cell cycle arrest of human naevi. Nature, 2005, 436, 720-724.
[62] Braig M., Lee S., Loddenkemper C., Rudolph C., Peters A. H., Schlegelberger B., Stein H., Dorken B., Jenuwein T., Schmitt C. A. Oncogene-induced senescence as an initial barrier in lymphoma development. Nature, 2005, 436, 660-665.
[63] Collado M., Gil J., Efeyan A., Guerra C., Schuhmacher A. J., Barradas M., Benguria A., Zaballos A., Flores J. M., Barbacid M., Beach D., Serrano M. Tumour biology: Senescence in premalignant tumours. Nature, 2005, 436, 642.
[64] Chen Z., Trotman L. C., Shaffer D., Lin H. K., Dotan Z. A., Niki M., Koutcher J. A., Scher H. I., Ludwig T., Gerald W., Cordon-Cardo C., Pandolfi P. P. Crucial role of p53-dependent cellular senescence in suppression of Pten-deficient tumorigenesis. Nature, 2005, 436, 725-730.
[65] Sharpless N. E., DePinho R. A. The INK4A/ARF locus and its two gene products. Curr Opin Genet Dev, 1999, 9, 22-30.
[66] Rizos H., Puig S., Badenas C., Malvehy J., Darmanian A. P., Jimenez L., Mila M., Kefford R. F. A melanoma-associated germline mutation in exon 1βinactivates p14ARF. Oncogene, 2001, 20, 5543-5547.
[67] Randerson-Moor J. A., Harland M., Williams S., Cuthbert-Heavens D., Sheridan E., Aveyard J., Sibley K., Whitaker L., Knowles M., Newton Bishop J., Bishop D. T. A germline deletion of p14ARF but notCDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet, 2001, 10, 55-62.
[68] Hewitt C., Lee Wu C., Evans G., Howell A., Elles R. G., Jordan R., Sloan P., Read A. P., Thakker, N. Serotonin 2C receptor agonists and the behavioural satiety sequence in mice. Hum Mol Genet, 2002, 11, 1273-1279.
[69] Kwong R. A., Kalish L. H., Nguyen T. V., Kench J. G., Bova R. J., Cole I. E., Musgrove E. A., Sutherland R. L. p14ARF protein expression is a predictor of both relapse and survival in squamous cell carcinoma of the anterior tongue. Clin Cancer Res, 2005, 11, 4107-4116.
[70] Esteller M., Gonzalez S., Risques R. A., Marcuello E., Mangues R., Germa J. R., Herman J. G., Capella G., Peinado M. A. K-ras and p16 aberrations confer poor prognosis in human colorectal cancer. J Clin Oncol, 2001, 19, 299-304.
[71] Esteller M., Tortola S., Toyota M., Capella G., Peinado M. A., Baylin S. B., Herman J. G. Hypermethylation-associated inactivation of p14(ARF) is independent of p16(INK4a) methylation and p53 mutational status. Cancer Res, 2000, 60, 129-133.
[72] Sato F., Harpaz N., Shibata D., Xu Y., Yin J., Mori Y., Zou T. T., Wang S., Desai K., Leytin A., Selaru F. M., Abraham J. M., Meltzer S. J. Hypermethylation of the p14ARF gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res, 2002, 62, 1148-1151.
[73] Burri N., Shaw P., Bouzourene H., Sordat I., Sordat B., Gillet M., Schorderet D., Bosman F. T., Chaubert P. Methylation silencing and mutations of the p14ARF and p16INK4a genes in colon cancer. Lab Invest, 2001, 81, 217-229.
[74]赵茜,陆融。磷脂酰肌醇3激酶-蛋白质丝氨酸苏氨酸激酶途径与肿瘤的关系国际肿瘤学杂志。2006,33(6):401-404.
[75] Ward S. G., Finan P. Isoform-specific phosphoinositide 3-kinase inhibitors as therapeutic agents. Curr Opin Pharmacol, 2003, 3: 426-434.
[76] Solit D. B., Basso A. D., Olshen A. B., Scher H. I., Rosen N. Inhibition of heat shock protein 90 function downregulates Akt kinase and sensitizes tumors to Taxol. Cancer Res, 2003, 63: 2139-2144.
[77]孙晓杰,黄常志。PI3K-Akt信号通路与肿瘤世界华人消化杂志。2006,14(3): 306-311.
[78] Katso R., Okkenhaug K., Ahmadi K., White S., Timms J., Waterfield M. D. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol, 2001, 17: 615-675.
[79] Maehama T., Taylor G. S., Dixon J. E. PTEN and myotubularin: Novel phosphoinositide phosphatases. Annu Rev Biochem, 2001, 70, 247-279.
[80] Maehama T., Dixon J. E., The tumor suppressor, PTEN/MMAC-1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. Biol Chem, 1998, 273, 13375-13378.
[81] Myers M. P., Pass I., Batty I. H., Van der Kaay J., Stolarov J. P., Hemmings B. A., Wigler M. H., Downes C. P., Tonks N. K. The lipid phosphatase activity of PTEN is critical for its tumor supressor function. Proc Natl Acad Sci, U.S.A., 1998, 95, 13513-13518 .
[82] Cantley L. C., Neel B. G. New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway. Proc Natl Acad Sci U.S.A., 1999, 96, 4240-4245.
[83] Franca-Koh J., Kamimura Y., Devreotes P. N. Leading-edge research: PtdIns(3,4,5)P3 and directed migration. Nat Cell Biol, 2007, 9, 15-17.
[84] Rossi D. J., Weissman I. L. Pten, Tumorigenesis, and Stem Cell Self-Renewal. Cell, 2006, 125, 229-231.
[85] Leslie N. R., Downes C. P. PTEN function: How normal cells control it and tumour cells lose it. Biochem J. 2004,382, 1-11.
[86] Sulis M. L., Parsons R. PTEN: From pathology to biology. Trends Cell Biol, 2003, 13, 478-483.
[87] Vazquez F., Sellers W. R. The PTEN tumor suppressor protein: An antagonist of phosphoinositide 3- kinase signaling. Biochim Biophys Acta, 2000, 1470, M21-35.
[88] Di Cristofano A., Pandolfi P. P. The multiple roles of PTEN in tumor suppression. Cell, 2000,100, 387-390.
[89] Lowe S. W., Sherr C. J. Tumor suppression by Ink4a-Arf: Progress and puzzles Curr Opin Genet Dev, 2003, 13, 77-83.
[90] Sherr C. J., McCormick F. The RB and p53 pathways in cancer. Cancer Cell, 2002, 2, 103-112.
[91] Pomerantz J., Schreiber-Agus N., Liegeois N. J., Silverman,A., Alland L., Chin L., Potes J., Chen K., Orlow I., Lee H. W., Cordon-Cardo C., DePinho R. A. The Ink4a tumor suppressor gene product, p19(Arf), interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell, 1998, 92, 713-723.
[92] Zhang Y., Xiong Y., Yarbrough W. G. ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways. Cell, 1998, 92, 725-734.
[93] Kamijo T., Weber J. D., Zambetti G., Zindy F., Roussel M. F., Sherr C. Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2. Proc Natl Acad Sci, USA, 1998, 95, 8292-8297.
[94] Stott F. J., Bates S., James M. C., McConnell B. B., Starborg M., Brookes S., Palmero I., Ryan K.,Hara E., Vousden K. H., Peters, G. The alternative product from the human CDKN2A locus, p14(ARF), participates in a regulatory feedback loop with p53 and MDM2. EMBO J, 1998, 17, 5001-5014.
[95] Radfar A., Unnikrishnan I., Lee H. W., DePinho R. A., Rosenberg N. p19Arf induces p53-dependent apoptosis during Abelson virus-mediated pre-B cell transformation. Proc Natl Acad Sci, USA, 1998,95, 13194-13199.
[96] Zindy F., Eischen C. M., Randle D. H., Kamijo T., Cleveland J. L., Sherr C. J., Roussel M. F. Myc signaling via the ARF tumor suppressor regulates p53-dependent apoptosis and immortalization. Genes Dev, 1998, 12, 2424-2433.
[97] de Stanchina E., McCurrach M. E., Zindy F., Shieh S. Y., Ferbeyre G., Samuelson A. V., Prives C., Roussel M. F., Sherr C. J., Lowe S. W. E1A signaling to p53 involves the p19(ARF) tumor suppressor. Genes Dev, 1998, 12, 2434-2442.
[98] Bates S., Phillips A. C., Clark P. A., Stott F., Peters G., Ludwig R. L., Vousden K. H. p14(ARF) links the tumour suppressors RB and p53 [5]. Nature, 1998, 395, 124-125.
[99] Sharpless N. E., Ramsey M. R., Balasubramanian P., Castrillon D. H., DePinho R. A. The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. Oncogene, 2004, 23, 379-385.
[100]卞寿庚。白血病[M]。中国医药科技出版社。2003
[101]仇霞芬。白血病[M]。中国医药科技出版社。2009
[102]宋善俊,陆道培,郝玉书(医学)。白血病[M]。湖北科学技术出版社。2004.
[103]刘新月。新编白血病细胞形态诊断学[M]。华中科技大学出版社。2008
[104] Jemal A., Thomas A., Murray T., Thun M. Cancer statistics 2002. CA Cancer J Clin 52:23, 2002.
[105]王亚平。造血干细胞生物学及其研究方法[M]。科学出版社。2007
[106] Orkin S. H., Zon LI. Snapshot: Hematopoiesis. Cell, 2008, 132.
[107] Tucker W. LeBien, Thomas F., Tedder B. lymphocytes: how they develop and function. Blood, 2008, 112(5), 1570-1580.
[108] Stephen L., Nutt, Barbara L., Kee. The Transcriptional Regulation of B Cell Lineage Commitment. DOI 10.1016/j.immuni.2007, 05, 010.
[109] Nutt S. L., Kee B. L. The transcriptional regulation of B cell lineage commitment. Immunity. 2007, 26, 715-725.
[110] Scott E.W., Simon M.C., Anastasi J., Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science, 1994, 265, 1573–1577.
[111] Bain G., et al. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell, 1994,79, 885-892.
[112] Lin H., Grosschedl R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature, 1995,376, 263-267.
[113] Seet C. S., Brumbaugh R. L., Kee B. L. Early B cell factor promotes B lymphopoiesis with reduced interleukin 7 responsiveness in the absence of E2A. J Exp Med, 2004, 199, 1689-1700.
[114] Johnson K., et al. Regulation of immunoglobulin light-chain recombination by the transcription factor IRF-4 and the attenuation of interleukin-7 signaling. Immunity. 2008, 28, 335-345.
[115] Richard R., Hardy, Paul W., Kincade, Kenneth Dorshkind. The Protean Nature of Cells in the B Lymphocyte Lineage. Immunity, 2007, 703-714.
[116] Klausner R.D. Studying cancer in the mouse. Oncogene, 1999, 18(38): 5249-5252.
[117] Desjatlais Jr,Berg JM Protein,1992,13:272
[118] Akira Suzuki, Tsuneyasu Kaisho, Minako Ohishi, et al. Critical Roles of Pten in B Cell Homeostasis and Immunoglobulin Class Switch Recombination[J]. J Exp Med, 2003, (197) 657-667.
[119] Suzuki A., de la Pompa J. L., Stambolic V., Elia A.J., Sasaki T., del Barco Barrantes I., Ho A., Wakeham A., Itie A., Khoo W., et al. High cancer susceptibility and embryonic lethality associated with mutation of the PTEN tumor suppressor gene in mice. Curr Biol, 1998, 8:1169-1178.
[120] Stambolic V., Suzuki A., de la Pompa J.L., Brothers G.M., Mirtsos C., Sasaki T., Ruland J., Penninger J.M., Siderovski D.P., Mak T.W. Negative regulation of PKB/Akt-dependent cell survival by the tumor suppressor PTEN. Cell, 1998, 95:29-39.
[121] Stambolic V., Tsao M.S., Macpherson D., Suzuki A., W.B. Chapman, Mak T.W. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten_/_ mice. Cancer Res. 2000, 60:3605–3611.
[122] Podsypanina K., Ellenson L.H., Nemes A., Gu J., Tamura M., Yamada K.M., Cordon-Cardo C., Catoretti G., Fisher P.E., Parsons R. Mutation of Pten/MMac-1 in mice causes neoplasia in multiple organ systems. Proc Natl Acad Sci, USA, 1999, 96:1563-568.
[123] Di Cristofano, A., Kotsi P., Peng Y.F., Cordon-Cardo C., Elkon K.B., Pandolfi P.P. Impaired Fas response and autoimmunity in Pten_/_ mice. Science, 1999, 285:2122–2125.
[124] Suzuki A., Yamaguchi M.T., Ohteki T., Sasaki T., Kaisho T., Kimura Y., Yoshida R., Wakeham A., Higuchi T., Fukumoto M., et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity, 2001, 14:523-534.
[125] Gronbaek K., Zeuthen J., Guldberg P., Ralfkiaer E., Hou-Jensen K. Alterations of the MMAC-1/PTEN gene in lymphoid malignancies. Blood, 1998, 91:4388-4390.
[126] Nakahara Y., Nagai H., Kinoshita T., Uchida T., Hatano S., Murate T., Saito H. Mutational analysis of the PTEN/MMAC-1 gene in non-Hodgkin’s lymphoma. Leukemia, 1998, 12:1277-1280.
[127] Hyun T., Yam A., Pece S., Xie X., Zhang J., Miki T., Gutkind J.S., Li W. Loss of PTEN expression leading to high Akt activation in human multiple myelomas. Blood, 2000, 96:3560-3568.
[128] Zheng H., Ying H., Yan H., et al. p53 and Pten control neural and glioma stem/progenitor cell renewal and differentiation. Nature, 2008, 455(7216): 1129-1133.
[129] Ralf Lesche, Matthias Groszer, Jing Gao, Ying Wang, Albee Messing, Hong Sun, Xin Liu, Hong Wu. Cre/loxP-Mediated Inactivation of the Murine Pten Tumor Suppressor Gene. Genesis, 2002,32:148-149.
[130] Zhuo L., Theis M., Alvarez-Maya I., Brenner M., Willecke K., Messing A. hGFAP-cre transgenic mice for manipulation of glial and neuronal function in vivo. Genesis, 2001, 31(2):85-94.
[131] Berger J. H., Bardeesy N. Modeling INK4/ARF Tumor Suppression in the Mouse. Current Molecular Medicine, 2007, 7, 63-75.
[132] Sharpless N. E., Bardeesy N., Lee K. H., Carrasco D., Castrillon D. H., Aguirre A. J., Wu E. A., Horner J. W., DePinho R. A. Loss of p16Ink4a with retention of p19 predisposes mice to tumorigenesis. Nature, 2001, 413, 86-91.
[133] Krimpenfort P., Quon K. C., Mooi W. J., Loonstra A., Berns A. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature, 2001, 413, 83-86.
[134] Kamijo T., Zindy F., Roussel M. F., Quelle D. E., Downing J. R., Ashmun R. A., Grosveld G., Sherr C. J. Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19(ARF). Cell, 1997, 91, 649-659.
[135] Sharpless N. E., Ramsey M. R., Balasubramanian P., Castrillon D. H., DePinho, R. A. () Oncogene, 2004, 23, 379-385
[136] Serrano M., Lee H., Chin L., Cordon-Cardo C., Beach D., DePinho, R. A. The differential impact of p16INK4a or p19ARF deficiency on cell growth and tumorigenesis. Cell, 1996, 85, 27-37.
[137] Haluska F. G., Tsao H., Wu H., Haluska F. S., Lazar A., Goel V. Genetic alterations in signaling pathways in melanoma Clin Cancer Res, 2006, 12, 2301s-2307s.
[138] Maher E. A., Furnari F. B., Bachoo R. M., Rowitch D. H., Louis D. N., Cavenee W. K., DePinho R. A. Malignant glioma: Genetics and biology of a grave matter. Genes Dev, 2001, 15, 1311-1333.
[139] Daniotti M., Oggionni M., Ranzani T., Vallacchi V., Campi V., Di Stasi D., Torre G. D., Perrone F.,Luoni C., Suardi S., Frattini M., Pilotti S., Anichini A., Tragni G., Parmiani G., Pierotti M. A., Rodolfo M. BRAF alterations are associated with complex mutational profiles in malignant melanoma. Oncogene, 2004, 23, 5968-5977.
[140] Daniel R. Carrasco, Tim Fenton, Kumar Sukhdeo, et al. The PTEN and INK4A/ARF tumor suppressors maintain myelolymphoid homeostasis and cooperate to constrain histiocytic sarcoma development in humans[J]. Cancer Cell, 2006(9), 379-390.
[141] Hobeika E., Thiemann S., Storch B. Testing gene function early in the B cell lineage in mb1-cre mice. PNAS, 2006, 103(37):13789-13794.
[142] Holliday R. A re-examination of the effects of ionizing radiation on lifespan and transformation of human diploid fibroblasts. Mut Res, 1991, 256 (2-6), pp. 295-302.
[143] Holliday R., Grigg G. W. DNA methylation and mutation. Mut Res,1993, 285:61.
[144] Cheng K. C., Loeb L. A., Genomic instability and tumor progression: Mechanistic considerations. Adv Cancer Res, 1993, 60:121.
[145] Reik W., Dean W., Walter J. Epigenetic reprogramming in mammalian development, Science, 2001, 293: 1089-1093
[146] Baylin S. B., Herman J. G., DNA hyperrnethylation in tumorigenesis: epigenetics joins genetics Trends Cenet, 2000, 16:168-174.
[147] Bender J. Cytosine methylation of repeated sequences in eukaryotes: the role of DNA pairing. Tremh Biochem Sci. 1998, 23: 252-256.
[148] Yoder J. A., Walsh C. P., Bestor T. H. Cytosine methylation and the ecology of intragenomic parasites Trends Cenet. 1997, 13:335-340.
[149]朱卫国。DNA甲基化,基因调控和癌症。世界华人消化杂志。2002, 10(6) 680-683.
[150] Kuang S. Q., Tong W. G., Yang H., et al. Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia. Leukemia, 2008, 22, 1529-1538.
[151] Costello J. F., Plass C.J. Aberrant methylation of genes in low-grade astrocytomas. Med Genet, 2001, 38(5): 285-303.
[152] Stirzaker C., Millar D.S., Paul C.L., Warnecke P.M., Harrison J., Vincent P.C., Frommer M., Clark S.J. Extensive DNA methylation spanning the Rb promoter in retinoblastoma tumors. Cancer Research, 1997, 57 (11), pp. 2229-2237.
[153] Adams R. L. Eukaryotic DNA methyltransferases - Structure and function. Bioessays, 1995, 17(2): 139-145.
[154] Fraga M.F., Rodríguez R., Ca?al M.J. Rapid quantification of DNA methylation by high performance capillary electrophoresis. Electrophoresis, 2000, 21 (14), pp. 2990-2994.
[155] Gonzalgo M.L., Liang G., Spruck III, C.H., Zingg J.-M., Rideout III W.M., Jones P.A. Identification and characterization of differentially methylated regions of genomic DNA by methylation-sensitive arbitrarily primed PCR1. Cancer Research, 1997, 57 (4), pp. 594-599.
[156] Frommer M., McDonald L. E., Millar D. S., Collis C. M., Watt F., Grigg G. W., Molloy P.L., Paul C.L. A genomic sequencing protocol that yields a positive display of 5- methylcytosine residues in individual DNA strands. Proc Natl Acad Sci, USA, 1992, 89(5): 1827-1831.
[157] Cindy A., Eads, Peter W., Laird. Combined Bisulfite Restriction Analysis (COBRA)[M]. Methods in Molecular Biology, volume 200:DNA Methylation Protocols.
[158] Aude Thiriot,et al. The Bw Cells, a Novel B Cell Population Conserved in the Whole Genus Mus. The Journal of Immunology, 2007, 179: 6568–6578.
[159] Wolfgang Walter, et al. Differential expression of alternative H2-M isoforms in B cells,dendritic cells and macrophages by proin ammatory cytokines[J]. Molecular Immunology 36 (1999) 733±743
[160] S-Q Kuang, W-G Tong, H Yang,et al. Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia[J]. Leukemia (2008) 22, 1529–1538
[161] Goodman, J.E., Bowman, E.D., Chanock, S.J., Alberg, A.J., Harris, C.C. Arachidonate lipoxygenase (ALOX) and cyclooxygenase (COX) polymorphisms and colon cancer risk[J]. 2004 Carcinogenesis 25 (12):2467-2472