PTEN和Notch1在急性髓性白血病中的表达及相关分析
|
摘要
研究背景
急性髓性白血病(acute myelocytic leukemia,AML)是严重危害患者健康的造血系统恶性肿瘤,其发病机制尚不十分清楚。PTEN是第一个被发现的具有磷酸化酶功能的抑癌基因,无论是在实体瘤还是在造血系统恶性肿瘤中,均存在PTEN功能的缺失。Notch信号通路在介导造血细胞增殖与分化过程中具有重要作用。PTEN和Notch均与恶性肿瘤的发生发展密切相关,二者之间存在一定联系。近年研究显示,PTEN和Notch1在急性髓性白血病中均有一定表达,但具体作用机制及其在疾病中的相互作用有待于进一步阐明。
目的
通过检测AML患者外周血单个核细胞中PTEN和Notch1基因的表达情况,探讨PTEN与Notch1在AML发病过程中的相互关系,为进一步揭示AML发病机制及其分子靶向治疗提供依据。
方法
选取AML患者共51例,分为初诊组和完全缓解(CR)组,并以22例健康志愿者作为对照。收集AML患者及对照组外周血单个核细胞,应用实时荧光定量逆转录聚合酶链反应(realtime Q-RT-PCR)方法对标本进行PTEN和Notch1基因表达的检测,同时以β-actin为内参照。应用SPSS统计学软件处理数据,采用Wilcoxon秩和检验、Spearman相关进行统计学分析,P＜0.05为差异有统计学意义。
结果
1.初诊AML患者外周血单个核细胞PTEN表达显著低于对照组(P＜0.05);也低于CR组,差异无统计学意义。
2.初诊AML患者外周血单个核细胞Notch1表达显著高于对照组(P＜0.05);也高于CR组,差异无统计学意义。
3.CR组AML患者外周血单个核细胞PTEN表达低于对照组,差异无统计学意义。
4.CR组AML患者外周血单个核细胞Notch1表达高于对照组,差异无统计学意义。
5.CR组和对照组PTEN与Notchl呈显著正相关(P＜0.01)。
结论
1.AML患者中存在PTEN和Notch1的异常表达,且与疾病状态有关,提示二者在AML发生发展中可能起一定作用。
2.AML完全缓解患者PTEN和Notch1存在相互联系。
Background
Acute myeloid leukemia(AML)is the common hematopoietic malignancy which endangers the health of patients severely.The pathogenesis of the disorder is not very clear. PTEN is the first tumor suppressor gene with the activity of phosphorylase.The loss of PTEN can be found in both solid tumors and hematopoietic malignancies.Notch signaling pathway plays an important role in the proliferation and differentiation of hematopoietic cells.PTEN and Notch signaling are the leading causes to the development of malignant tumors,and there are some relations between of them.It is showed that abnormal expression of PTEN or Notch1 can be tested in acute myeloid leukemia in recent years,but the mechanisms and relationships in the pathogenesis of AML need to be further studied.
Objective
To investigate the roles and mutual relations of PTEN and Notch1 in the pathogenesis of AML,we detect the expression level of PTEN and Notch1 mRNA of AML patients' peripheral blood mononuclear cells(PBMs),so as to reveal the pathogenesis of AML and provide the basis for molecular targeted therapy.
Methods
We selected 51 AML patients,divided into the newly diagnosed group and the complete remission(CR)group,and selected 22 healthy volunteers as control group.Collecting peripheral blood mononuclear cells of AML patients and the control group,and using the real-time Q-RT-PCR to detect the mRNA expression of PTEN and Notch1,andβ-actin were detected as internal control.We used SPSS statistical software,and Wilcoxon rank-sum test and Spearman rank correlation was applied.P＜0.05 is the statistical significance differences.
Results
1.The expression of PTEN in peripheral blood mononuclear cells of newly diagnosed group patients were significantly lower than that of the control group(P＜0.05);and also lower than that of CR group,but there was no significant difference.
2.The expression of Notch1 in peripheral blood mononuclear cells of newly diagnosed group patients were significantly higher than that of the control group(P＜0.05);and also higher than that of CR group,but there was no significant difference.
3.The expression of PTEN in peripheral blood mononuclear cells of CR group patients was decreased,but there was no significant difference.
4.The expression of Notch1 in peripheral blood mononuclear cells of CR group patients was increased,but there was no significant difference.
5.PTEN and Notch1 in CR group and control group were positive correlation(P＜0.01).
Conclusions
1.The abnormal expression of PTEN and Notch1 could be found in AML patients,and be related to the disease status,suggesting that they may both play important roles in the development of AML.
2.PTEN and Notch1 are interrelated in AML patient with complete remission.
急性髓性白血病(acute myelocytic leukemia,AML)是严重危害患者健康的造血系统恶性肿瘤,其发病机制尚不十分清楚。PTEN是第一个被发现的具有磷酸化酶功能的抑癌基因,无论是在实体瘤还是在造血系统恶性肿瘤中,均存在PTEN功能的缺失。Notch信号通路在介导造血细胞增殖与分化过程中具有重要作用。PTEN和Notch均与恶性肿瘤的发生发展密切相关,二者之间存在一定联系。近年研究显示,PTEN和Notch1在急性髓性白血病中均有一定表达,但具体作用机制及其在疾病中的相互作用有待于进一步阐明。
目的
通过检测AML患者外周血单个核细胞中PTEN和Notch1基因的表达情况,探讨PTEN与Notch1在AML发病过程中的相互关系,为进一步揭示AML发病机制及其分子靶向治疗提供依据。
方法
选取AML患者共51例,分为初诊组和完全缓解(CR)组,并以22例健康志愿者作为对照。收集AML患者及对照组外周血单个核细胞,应用实时荧光定量逆转录聚合酶链反应(realtime Q-RT-PCR)方法对标本进行PTEN和Notch1基因表达的检测,同时以β-actin为内参照。应用SPSS统计学软件处理数据,采用Wilcoxon秩和检验、Spearman相关进行统计学分析,P＜0.05为差异有统计学意义。
结果
1.初诊AML患者外周血单个核细胞PTEN表达显著低于对照组(P＜0.05);也低于CR组,差异无统计学意义。
2.初诊AML患者外周血单个核细胞Notch1表达显著高于对照组(P＜0.05);也高于CR组,差异无统计学意义。
3.CR组AML患者外周血单个核细胞PTEN表达低于对照组,差异无统计学意义。
4.CR组AML患者外周血单个核细胞Notch1表达高于对照组,差异无统计学意义。
5.CR组和对照组PTEN与Notchl呈显著正相关(P＜0.01)。
结论
1.AML患者中存在PTEN和Notch1的异常表达,且与疾病状态有关,提示二者在AML发生发展中可能起一定作用。
2.AML完全缓解患者PTEN和Notch1存在相互联系。
Background
Acute myeloid leukemia(AML)is the common hematopoietic malignancy which endangers the health of patients severely.The pathogenesis of the disorder is not very clear. PTEN is the first tumor suppressor gene with the activity of phosphorylase.The loss of PTEN can be found in both solid tumors and hematopoietic malignancies.Notch signaling pathway plays an important role in the proliferation and differentiation of hematopoietic cells.PTEN and Notch signaling are the leading causes to the development of malignant tumors,and there are some relations between of them.It is showed that abnormal expression of PTEN or Notch1 can be tested in acute myeloid leukemia in recent years,but the mechanisms and relationships in the pathogenesis of AML need to be further studied.
Objective
To investigate the roles and mutual relations of PTEN and Notch1 in the pathogenesis of AML,we detect the expression level of PTEN and Notch1 mRNA of AML patients' peripheral blood mononuclear cells(PBMs),so as to reveal the pathogenesis of AML and provide the basis for molecular targeted therapy.
Methods
We selected 51 AML patients,divided into the newly diagnosed group and the complete remission(CR)group,and selected 22 healthy volunteers as control group.Collecting peripheral blood mononuclear cells of AML patients and the control group,and using the real-time Q-RT-PCR to detect the mRNA expression of PTEN and Notch1,andβ-actin were detected as internal control.We used SPSS statistical software,and Wilcoxon rank-sum test and Spearman rank correlation was applied.P＜0.05 is the statistical significance differences.
Results
1.The expression of PTEN in peripheral blood mononuclear cells of newly diagnosed group patients were significantly lower than that of the control group(P＜0.05);and also lower than that of CR group,but there was no significant difference.
2.The expression of Notch1 in peripheral blood mononuclear cells of newly diagnosed group patients were significantly higher than that of the control group(P＜0.05);and also higher than that of CR group,but there was no significant difference.
3.The expression of PTEN in peripheral blood mononuclear cells of CR group patients was decreased,but there was no significant difference.
4.The expression of Notch1 in peripheral blood mononuclear cells of CR group patients was increased,but there was no significant difference.
5.PTEN and Notch1 in CR group and control group were positive correlation(P＜0.01).
Conclusions
1.The abnormal expression of PTEN and Notch1 could be found in AML patients,and be related to the disease status,suggesting that they may both play important roles in the development of AML.
2.PTEN and Notch1 are interrelated in AML patient with complete remission.
引文
1 Redaelli A,Lee JM,Stephens JM,et al.Epidemiology and clinical burden of acute myeloid leukemia.Expert Rev Anticancer Ther,2003,3:695-710.
2 纪春岩,马道新,等.Delta4的功能性研究及与其他Notch配体的比较.山东大学学报,2003,4:477-480.
3 Chiaramonte R,Basile A,Tassi E,et al.A wide role for NOTCH1 signaling in acute leukemia.Cancer Lett,2005,219:113-20.
4 Palomero T,Sulis ML,Cortina M,et al.Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.Nat Med,2007,13:1203-10.
5 Bennett JM,Catovsky D,Daniel MT,et al.Proposal for the classification of the acute leukemias.French-American-British(FAB)cooperative group.Br J Haematol,1976,33:451-458.
6 张之南,沈悌.血液病诊断及疗效标准.北京:科技技术出版,2007.106-113.
7 Gibson UE,Heid CA,Williams PM.A novel method for real time quantitative RT-PCR.Genome Res,1996,6:995-1001.
8 Heid CA,Stevens J,Livak KJ,et al.Real time quantitative PCR.Genome Res,1996,6:986-94.
9 Li DM,Sun H.TEP1,encoded by a candidate tumor suppressor locus,is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.Cancer Res,1997,57:2124-9.
10 Li J,Yen C,Liaw D,et al.PTEN,a putative protein tyrosine phosphatase gene mutated in human brain,breast,and prostate cancer.Science,1997,275:1943-7.
11 Steck PA,Pershouse MA,Jasser SA,et al.Identification of a candidate tumour suppressor gene,MMAC1,at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet,1997,15:356-62.
12 Vazquez F,Ramaswamy S,Nakamura N,et al.Phosphorylation of the PTEN tail regulates protein stability and function.Mol Cell Biol,2000,20:5010-8.
13 Myers MP, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A, 1997,94:9052-7.
14 Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem, 1999,263:605-11.
15 Georgescu MM, Kirsch KH, Kaloudis P, et al. Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. Cancer Res, 2000,60:7033-8.
16 Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene, 1999,18:7034-45.
17 Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev, 1999,13:2905-27.
18 Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci, 2002,27:462-7.
19 Comer FI, Parent CA. PI 3-kinases and PTEN: how opposites chemoattract. Cell, 2002,109:541-4.
20 Chung CY, Funamoto S, Firtel RA. Signaling pathways controlling cell polarity and chemotaxis. Trends Biochem Sci, 2001,26:557-66.
21 Backman S, Stambolic V, Mak T. PTEN function in mammalian cell size regulation. Curr Opin Neurobiol, 2002,12:516-22.
22 Verdu J, Buratovich MA, Wilder EL, et al. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat Cell Biol, 1999,1:500-6.
23 Suzuki A, Kaisho T, Ohishi M, et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J Exp Med, 2003,197:657-67.
24 Suzuki A, Yamaguchi MT, Ohteki T, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity, 2001,14:523-34.
25 Stambolic V, Tsao MS, Macpherson D, et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res, 2000,60:3605-11.
26 Crackower MA, Oudit GY, Kozieradzki I, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell, 2002,110:737-49.
27 Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci, 2001,114:2375-82.
28 Higuchi M, Masuyama N, Fukui Y, et al. Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells. Curr Biol, 2001,11:1958-62.
29 Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature, 2006,441:475-82.
30 Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature, 2006,441:518-22.
31 Aggerholm A, Gronbaek K, Guldberg P, et al. Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol, 2000,65:109-13.
32 Leupin N, Cenni B, Novak U, et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). Br J Haematol, 2003,121:97-100.
33 Shen Q, Chen Z, Liu XP, et al. [Expression of PTEN mRNA in acute leukemia and its clinical significance]. Zhonghua Xue Ye Xue Za Zhi, 2005,26:493-6.
34 Seminario MC, Precht P, Wersto RP, et al. PTEN expression in PTEN-null leukaemic T cell lines leads to reduced proliferation via slowed cell cycle progression. Oncogene, 2003,22:8195-204.
35 Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol, 2006,7:285-94.
36 Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med, 1996,183:2283-91.
37 Jeffries S, Robbins DJ, Capobianco AJ. Characterization of a high-molecular-weight Notch complex in the nucleus of Notch(ic)-transformed RKE cells and in a human T-cell leukemia cell line. Mol Cell Biol, 2002,22:3927-41.
38 Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 2004,306:269-71.
39 Lee SY, Kumano K, Masuda S, et al. Mutations of the Notchl gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia, 2005,19:1841-3.
40 Carlesso N, Aster JC, Sklar J, et al. Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood, 1999,93:838-48.
41 Tohda S, Nara N. Expression of Notchl and Jaggedl proteins in acute myeloid leukemia cells. Leuk Lymphoma, 2001,42:467-72.
42 Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell, 2007,12:411-3.
43 Calzavara E, Chiaramonte R, Cesana D, et al. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem, 2007.
44 Chappell WH, Green TD, Spengeman JD, et al. Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1. Cell Cycle, 2005,4:1389-95.
45 Whelan JT, Forbes SL, Bertrand FE. CBF-1 (RBP-J kappa) binds to the PTEN promoter and regulates PTEN gene expression. Cell Cycle, 2007,6:80-4.
1 Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997,57:2124-9.
2 Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997,275:1943-7.
3 Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 1997,15:356-62.
4 Vazquez F, Ramaswamy S, Nakamura N, et al. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol, 2000,20:5010-8.
5 Myers MP, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A, 1997,94:9052-7.
6 Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem, 1999,263:605-11.
7 Georgescu MM, Kirsch KH, Kaloudis P, et al. Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. Cancer Res, 2000,60:7033-8.
8 Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer, 2006,6:184-92.
9 Rosen N, She QB. AKT and cancer--is it all mTOR?. Cancer Cell, 2006,10:254-6.
10 Urano J, Sato T, Matsuo T, et al. Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc Natl Acad Sci U S A, 2007,104:3514-9.
11 Takahashi K, Murakami M, Yamanaka S. Role of the phosphoinositide 3-kinase pathway in mouse embryonic stem (ES) cells. Biochem Soc Trans, 2005,33:1522-5.
12 Zhang H, Bajraszewski N, Wu E, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest, 2007,117:730-8.
13 Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res, 2005,65:2554-9.
14 Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev, 2005,24:273-85.
15 Gu J, Tamura M, Yamada KM. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol, 1998,143:1375-83.
16 Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science, 1998,280:1614-7.
17 Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci, 2001,114:2375-82.
18 Tamura M, Gu J, Takino T, et al. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res, 1999,59:442-9.
19 Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature, 2006,441:475-82.
20 Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature, 2006,441:518-22.
21 Aggerholm A, Gronbaek K, Guldberg P, et al. Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol, 2000,65:109-13.
22 Leupin N, Cenni B, Novak U, et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). Br J Haematol, 2003,121:97-100.
23 Shen Q, Chen Z, Liu XP, et al. [Expression of PTEN mRNA in acute leukemia and its clinical significance]. Zhonghua Xue Ye Xue Za Zhi, 2005,26:493-6.
24 Seminario MC, Precht P, Wersto RP, et al. PTEN expression in PTEN-null leukaemic T cell lines leads to reduced proliferation via slowed cell cycle progression. Oncogene, 2003,22:8195-204.
25 Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol, 2006,7:285-94.
26 Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med, 2007,13:1203-10.
27 Lee YR, Yu HN, Noh EM, et al. TNF-alpha upregulates PTEN via NF-kappaB signaling pathways in human leukemic cells. Exp Mol Med, 2007,39:121-7.
28 Nakahara Y, Nagai H, Kinoshita T, et al. Mutational analysis of the PTEN/MMACl gene in non-Hodgkin's lymphoma. Leukemia, 1998,12:1277-80.
29 Sakai A, Thieblemont C, Wellmann A, et al. PTEN gene alterations in lymphoid neoplasms. Blood, 1998,92:3410-5.
30 Uner AH, Saglam A, Han U, et al. PTEN and p27 expression in mature T-cell and NK-cell neoplasms. Leuk Lymphoma, 2005,46:1463-70.
31 Wendel HG, Malina A, Zhao Z, et al. Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res, 2006,66:7639-46.
32 Chang H, Qi XY, Claudio J, et al. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk Res, 2006,30:262-5.
33 Ge NL, Rudikoff S. Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo. Oncogene, 2000,19:4091-5.
34 Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res, 2002,62:5027-34.
35 Zhang J, Choi Y, Mavromatis B, et al. Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway. Oncogene, 2003,22:6289-95.
2 纪春岩,马道新,等.Delta4的功能性研究及与其他Notch配体的比较.山东大学学报,2003,4:477-480.
3 Chiaramonte R,Basile A,Tassi E,et al.A wide role for NOTCH1 signaling in acute leukemia.Cancer Lett,2005,219:113-20.
4 Palomero T,Sulis ML,Cortina M,et al.Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia.Nat Med,2007,13:1203-10.
5 Bennett JM,Catovsky D,Daniel MT,et al.Proposal for the classification of the acute leukemias.French-American-British(FAB)cooperative group.Br J Haematol,1976,33:451-458.
6 张之南,沈悌.血液病诊断及疗效标准.北京:科技技术出版,2007.106-113.
7 Gibson UE,Heid CA,Williams PM.A novel method for real time quantitative RT-PCR.Genome Res,1996,6:995-1001.
8 Heid CA,Stevens J,Livak KJ,et al.Real time quantitative PCR.Genome Res,1996,6:986-94.
9 Li DM,Sun H.TEP1,encoded by a candidate tumor suppressor locus,is a novel protein tyrosine phosphatase regulated by transforming growth factor beta.Cancer Res,1997,57:2124-9.
10 Li J,Yen C,Liaw D,et al.PTEN,a putative protein tyrosine phosphatase gene mutated in human brain,breast,and prostate cancer.Science,1997,275:1943-7.
11 Steck PA,Pershouse MA,Jasser SA,et al.Identification of a candidate tumour suppressor gene,MMAC1,at chromosome 10q23.3 that is mutated in multiple advanced cancers.Nat Genet,1997,15:356-62.
12 Vazquez F,Ramaswamy S,Nakamura N,et al.Phosphorylation of the PTEN tail regulates protein stability and function.Mol Cell Biol,2000,20:5010-8.
13 Myers MP, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A, 1997,94:9052-7.
14 Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem, 1999,263:605-11.
15 Georgescu MM, Kirsch KH, Kaloudis P, et al. Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. Cancer Res, 2000,60:7033-8.
16 Lu Y, Lin YZ, LaPushin R, et al. The PTEN/MMAC1/TEP tumor suppressor gene decreases cell growth and induces apoptosis and anoikis in breast cancer cells. Oncogene, 1999,18:7034-45.
17 Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev, 1999,13:2905-27.
18 Mayo LD, Donner DB. The PTEN, Mdm2, p53 tumor suppressor-oncoprotein network. Trends Biochem Sci, 2002,27:462-7.
19 Comer FI, Parent CA. PI 3-kinases and PTEN: how opposites chemoattract. Cell, 2002,109:541-4.
20 Chung CY, Funamoto S, Firtel RA. Signaling pathways controlling cell polarity and chemotaxis. Trends Biochem Sci, 2001,26:557-66.
21 Backman S, Stambolic V, Mak T. PTEN function in mammalian cell size regulation. Curr Opin Neurobiol, 2002,12:516-22.
22 Verdu J, Buratovich MA, Wilder EL, et al. Cell-autonomous regulation of cell and organ growth in Drosophila by Akt/PKB. Nat Cell Biol, 1999,1:500-6.
23 Suzuki A, Kaisho T, Ohishi M, et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J Exp Med, 2003,197:657-67.
24 Suzuki A, Yamaguchi MT, Ohteki T, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity, 2001,14:523-34.
25 Stambolic V, Tsao MS, Macpherson D, et al. High incidence of breast and endometrial neoplasia resembling human Cowden syndrome in pten+/- mice. Cancer Res, 2000,60:3605-11.
26 Crackower MA, Oudit GY, Kozieradzki I, et al. Regulation of myocardial contractility and cell size by distinct PI3K-PTEN signaling pathways. Cell, 2002,110:737-49.
27 Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci, 2001,114:2375-82.
28 Higuchi M, Masuyama N, Fukui Y, et al. Akt mediates Rac/Cdc42-regulated cell motility in growth factor-stimulated cells and in invasive PTEN knockout cells. Curr Biol, 2001,11:1958-62.
29 Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature, 2006,441:475-82.
30 Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature, 2006,441:518-22.
31 Aggerholm A, Gronbaek K, Guldberg P, et al. Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol, 2000,65:109-13.
32 Leupin N, Cenni B, Novak U, et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). Br J Haematol, 2003,121:97-100.
33 Shen Q, Chen Z, Liu XP, et al. [Expression of PTEN mRNA in acute leukemia and its clinical significance]. Zhonghua Xue Ye Xue Za Zhi, 2005,26:493-6.
34 Seminario MC, Precht P, Wersto RP, et al. PTEN expression in PTEN-null leukaemic T cell lines leads to reduced proliferation via slowed cell cycle progression. Oncogene, 2003,22:8195-204.
35 Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol, 2006,7:285-94.
36 Pear WS, Aster JC, Scott ML, et al. Exclusive development of T cell neoplasms in mice transplanted with bone marrow expressing activated Notch alleles. J Exp Med, 1996,183:2283-91.
37 Jeffries S, Robbins DJ, Capobianco AJ. Characterization of a high-molecular-weight Notch complex in the nucleus of Notch(ic)-transformed RKE cells and in a human T-cell leukemia cell line. Mol Cell Biol, 2002,22:3927-41.
38 Weng AP, Ferrando AA, Lee W, et al. Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia. Science, 2004,306:269-71.
39 Lee SY, Kumano K, Masuda S, et al. Mutations of the Notchl gene in T-cell acute lymphoblastic leukemia: analysis in adults and children. Leukemia, 2005,19:1841-3.
40 Carlesso N, Aster JC, Sklar J, et al. Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics. Blood, 1999,93:838-48.
41 Tohda S, Nara N. Expression of Notchl and Jaggedl proteins in acute myeloid leukemia cells. Leuk Lymphoma, 2001,42:467-72.
42 Gutierrez A, Look AT. NOTCH and PI3K-AKT pathways intertwined. Cancer Cell, 2007,12:411-3.
43 Calzavara E, Chiaramonte R, Cesana D, et al. Reciprocal regulation of Notch and PI3K/Akt signalling in T-ALL cells In Vitro. J Cell Biochem, 2007.
44 Chappell WH, Green TD, Spengeman JD, et al. Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1. Cell Cycle, 2005,4:1389-95.
45 Whelan JT, Forbes SL, Bertrand FE. CBF-1 (RBP-J kappa) binds to the PTEN promoter and regulates PTEN gene expression. Cell Cycle, 2007,6:80-4.
1 Li DM, Sun H. TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res, 1997,57:2124-9.
2 Li J, Yen C, Liaw D, et al. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science, 1997,275:1943-7.
3 Steck PA, Pershouse MA, Jasser SA, et al. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet, 1997,15:356-62.
4 Vazquez F, Ramaswamy S, Nakamura N, et al. Phosphorylation of the PTEN tail regulates protein stability and function. Mol Cell Biol, 2000,20:5010-8.
5 Myers MP, Stolarov JP, Eng C, et al. P-TEN, the tumor suppressor from human chromosome 10q23, is a dual-specificity phosphatase. Proc Natl Acad Sci U S A, 1997,94:9052-7.
6 Besson A, Robbins SM, Yong VW. PTEN/MMAC1/TEP1 in signal transduction and tumorigenesis. Eur J Biochem, 1999,263:605-11.
7 Georgescu MM, Kirsch KH, Kaloudis P, et al. Stabilization and productive positioning roles of the C2 domain of PTEN tumor suppressor. Cancer Res, 2000,60:7033-8.
8 Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer, 2006,6:184-92.
9 Rosen N, She QB. AKT and cancer--is it all mTOR?. Cancer Cell, 2006,10:254-6.
10 Urano J, Sato T, Matsuo T, et al. Point mutations in TOR confer Rheb-independent growth in fission yeast and nutrient-independent mammalian TOR signaling in mammalian cells. Proc Natl Acad Sci U S A, 2007,104:3514-9.
11 Takahashi K, Murakami M, Yamanaka S. Role of the phosphoinositide 3-kinase pathway in mouse embryonic stem (ES) cells. Biochem Soc Trans, 2005,33:1522-5.
12 Zhang H, Bajraszewski N, Wu E, et al. PDGFRs are critical for PI3K/Akt activation and negatively regulated by mTOR. J Clin Invest, 2007,117:730-8.
13 Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res, 2005,65:2554-9.
14 Robertson GP. Functional and therapeutic significance of Akt deregulation in malignant melanoma. Cancer Metastasis Rev, 2005,24:273-85.
15 Gu J, Tamura M, Yamada KM. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol, 1998,143:1375-83.
16 Tamura M, Gu J, Matsumoto K, et al. Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science, 1998,280:1614-7.
17 Yamada KM, Araki M. Tumor suppressor PTEN: modulator of cell signaling, growth, migration and apoptosis. J Cell Sci, 2001,114:2375-82.
18 Tamura M, Gu J, Takino T, et al. Tumor suppressor PTEN inhibition of cell invasion, migration, and growth: differential involvement of focal adhesion kinase and p130Cas. Cancer Res, 1999,59:442-9.
19 Yilmaz OH, Valdez R, Theisen BK, et al. Pten dependence distinguishes haematopoietic stem cells from leukaemia-initiating cells. Nature, 2006,441:475-82.
20 Zhang J, Grindley JC, Yin T, et al. PTEN maintains haematopoietic stem cells and acts in lineage choice and leukaemia prevention. Nature, 2006,441:518-22.
21 Aggerholm A, Gronbaek K, Guldberg P, et al. Mutational analysis of the tumour suppressor gene MMAC1/PTEN in malignant myeloid disorders. Eur J Haematol, 2000,65:109-13.
22 Leupin N, Cenni B, Novak U, et al. Disparate expression of the PTEN gene: a novel finding in B-cell chronic lymphocytic leukaemia (B-CLL). Br J Haematol, 2003,121:97-100.
23 Shen Q, Chen Z, Liu XP, et al. [Expression of PTEN mRNA in acute leukemia and its clinical significance]. Zhonghua Xue Ye Xue Za Zhi, 2005,26:493-6.
24 Seminario MC, Precht P, Wersto RP, et al. PTEN expression in PTEN-null leukaemic T cell lines leads to reduced proliferation via slowed cell cycle progression. Oncogene, 2003,22:8195-204.
25 Witzig TE, Kaufmann SH. Inhibition of the phosphatidylinositol 3-kinase/mammalian target of rapamycin pathway in hematologic malignancies. Curr Treat Options Oncol, 2006,7:285-94.
26 Palomero T, Sulis ML, Cortina M, et al. Mutational loss of PTEN induces resistance to NOTCH1 inhibition in T-cell leukemia. Nat Med, 2007,13:1203-10.
27 Lee YR, Yu HN, Noh EM, et al. TNF-alpha upregulates PTEN via NF-kappaB signaling pathways in human leukemic cells. Exp Mol Med, 2007,39:121-7.
28 Nakahara Y, Nagai H, Kinoshita T, et al. Mutational analysis of the PTEN/MMACl gene in non-Hodgkin's lymphoma. Leukemia, 1998,12:1277-80.
29 Sakai A, Thieblemont C, Wellmann A, et al. PTEN gene alterations in lymphoid neoplasms. Blood, 1998,92:3410-5.
30 Uner AH, Saglam A, Han U, et al. PTEN and p27 expression in mature T-cell and NK-cell neoplasms. Leuk Lymphoma, 2005,46:1463-70.
31 Wendel HG, Malina A, Zhao Z, et al. Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res, 2006,66:7639-46.
32 Chang H, Qi XY, Claudio J, et al. Analysis of PTEN deletions and mutations in multiple myeloma. Leuk Res, 2006,30:262-5.
33 Ge NL, Rudikoff S. Expression of PTEN in PTEN-deficient multiple myeloma cells abolishes tumor growth in vivo. Oncogene, 2000,19:4091-5.
34 Shi Y, Gera J, Hu L, et al. Enhanced sensitivity of multiple myeloma cells containing PTEN mutations to CCI-779. Cancer Res, 2002,62:5027-34.
35 Zhang J, Choi Y, Mavromatis B, et al. Preferential killing of PTEN-null myelomas by PI3K inhibitors through Akt pathway. Oncogene, 2003,22:6289-95.