PTEN 是 CML 干细胞和 BCR-ABL 诱导的小鼠白血病中的肿瘤抑制因子。
PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice.
机构信息
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA.
出版信息
Blood. 2010 Jan 21;115(3):626-35. doi: 10.1182/blood-2009-06-228130. Epub 2009 Nov 18.
Abstract
The tumor suppressor gene phosphatase and tensin homolog (PTEN) is inactivated in many human cancers. However, it is unknown whether PTEN functions as a tumor suppressor in human Philadelphia chromosome-positive leukemia that includes chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) and is induced by the BCR-ABL oncogene. By using our mouse model of BCR-ABL-induced leukemias, we show that Pten is down-regulated by BCR-ABL in leukemia stem cells in CML and that PTEN deletion causes acceleration of CML development. In addition, overexpression of PTEN delays the development of CML and B-ALL and prolongs survival of leukemia mice. PTEN suppresses leukemia stem cells and induces cell-cycle arrest of leukemia cells. Moreover, PTEN suppresses B-ALL development through regulating its downstream gene Akt1. These results demonstrate a critical role of PTEN in BCR-ABL-induced leukemias and suggest a potential strategy for the treatment of Philadelphia chromosome-positive leukemia.
摘要
抑癌基因磷酸酶和张力蛋白同源物（PTEN）在许多人类癌症中失活。然而，目前尚不清楚 PTEN 是否在人类费城染色体阳性白血病（包括慢性髓系白血病（CML）和 B 细胞急性淋巴细胞白血病（B-ALL））中作为肿瘤抑制因子发挥作用，而费城染色体阳性白血病是由 BCR-ABL 癌基因诱导的。通过使用我们的 BCR-ABL 诱导白血病的小鼠模型，我们表明 Pten 在 CML 中的白血病干细胞中被 BCR-ABL 下调，并且 PTEN 缺失导致 CML 发展加速。此外，PTEN 的过表达延迟了 CML 和 B-ALL 的发展，并延长了白血病小鼠的存活时间。PTEN 抑制白血病干细胞并诱导白血病细胞的细胞周期停滞。此外，PTEN 通过调节其下游基因 Akt1 来抑制 B-ALL 的发展。这些结果表明 PTEN 在 BCR-ABL 诱导的白血病中具有重要作用，并为治疗费城染色体阳性白血病提供了一种潜在的策略。
相似文献
1
PTEN is a tumor suppressor in CML stem cells and BCR-ABL-induced leukemias in mice.PTEN 是 CML 干细胞和 BCR-ABL 诱导的小鼠白血病中的肿瘤抑制因子。
Blood. 2010 Jan 21;115(3):626-35. doi: 10.1182/blood-2009-06-228130. Epub 2009 Nov 18.
2
Bcr-Abl efficiently induces a myeloproliferative disease and production of excess interleukin-3 and granulocyte-macrophage colony-stimulating factor in mice: a novel model for chronic myelogenous leukemia.Bcr-Abl可有效诱导小鼠发生骨髓增殖性疾病，并产生过量的白细胞介素-3和粒细胞-巨噬细胞集落刺激因子：一种慢性粒细胞白血病的新模型。
Blood. 1998 Nov 15;92(10):3829-40.
3
A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA.一种长链非编码RNA通过作为竞争性内源性RNA来关键调控Bcr-Abl介导的细胞转化。
Oncogene. 2015 Apr 2;34(14):1768-79. doi: 10.1038/onc.2014.131. Epub 2014 May 19.
4
PTEN Is Fundamental for Elimination of Leukemia Stem Cells Mediated by GSK126 Targeting EZH2 in Chronic Myelogenous Leukemia.PTEN 对 GSK126 靶向 EZH2 消除慢性髓性白血病中白血病干细胞至关重要。
Clin Cancer Res. 2018 Jan 1;24(1):145-157. doi: 10.1158/1078-0432.CCR-17-1533. Epub 2017 Oct 25.
5
Gadd45a deficiency accelerates BCR-ABL driven chronic myelogenous leukemia.Gadd45a基因缺陷会加速BCR-ABL驱动的慢性粒细胞白血病进程。
Oncotarget. 2017 Feb 14;8(7):10809-10821. doi: 10.18632/oncotarget.14580.
6
Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models.Fyn 在小鼠骨髓移植模型中 Bcr-Abl 诱导的白血病发生中不是必需的。
Int J Hematol. 2012 Feb;95(2):167-75. doi: 10.1007/s12185-011-0994-5. Epub 2011 Dec 22.
7
Inhibitory effects of omacetaxine on leukemic stem cells and BCR-ABL-induced chronic myeloid leukemia and acute lymphoblastic leukemia in mice.奥马西他辛对小鼠白血病干细胞以及BCR-ABL诱导的慢性髓性白血病和急性淋巴细胞白血病的抑制作用。
Leukemia. 2009 Aug;23(8):1446-54. doi: 10.1038/leu.2009.52. Epub 2009 Mar 26.
8
Evi1 defines leukemia-initiating capacity and tyrosine kinase inhibitor resistance in chronic myeloid leukemia.Evi1决定慢性髓性白血病的白血病起始能力和酪氨酸激酶抑制剂耐药性。
Oncogene. 2014 Oct 16;33(42):5028-38. doi: 10.1038/onc.2014.108. Epub 2014 Apr 21.
9
Essential role for telomerase in chronic myeloid leukemia induced by BCR-ABL in mice.端粒酶在小鼠BCR-ABL诱导的慢性髓性白血病中的重要作用。
Oncotarget. 2012 Mar;3(3):261-6. doi: 10.18632/oncotarget.461.
10
Bmi1 reprograms CML B-lymphoid progenitors to become B-ALL-initiating cells.BMI1 将 CML B 淋巴样祖细胞重编程为 B-ALL 起始细胞。
Blood. 2012 Jan 12;119(2):494-502. doi: 10.1182/blood-2011-06-359232. Epub 2011 Nov 18.
引用本文的文献
1
Identification of ubiquitination-related hub genes in chronic myeloid leukemia cell by bioinformatics analysis.通过生物信息学分析鉴定慢性粒细胞白血病细胞中与泛素化相关的枢纽基因。
J Cancer. 2024 May 20;15(12):3750-3759. doi: 10.7150/jca.96405. eCollection 2024.
2
A new perspective on hematological malignancies: m6A modification in immune microenvironment.血液系统恶性肿瘤的新视角：免疫微环境中的m6A修饰
Front Immunol. 2024 May 28;15:1374390. doi: 10.3389/fimmu.2024.1374390. eCollection 2024.
3
Signaling pathways governing the behaviors of leukemia stem cells.调控白血病干细胞行为的信号通路。
Genes Dis. 2023 Mar 23;11(2):830-846. doi: 10.1016/j.gendis.2023.01.008. eCollection 2024 Mar.
4
TSPAN32 suppresses chronic myeloid leukemia pathogenesis and progression by stabilizing PTEN.TSPAN32 通过稳定 PTEN 抑制慢性髓性白血病的发病和进展。
Signal Transduct Target Ther. 2023 Mar 1;8(1):90. doi: 10.1038/s41392-022-01290-7.
5
Treatment-Free Remission in Chronic Myeloid Leukemia and New Approaches by Targeting Leukemia Stem Cells.慢性髓性白血病的无治疗缓解及靶向白血病干细胞的新方法
Front Oncol. 2021 Oct 28;11:769730. doi: 10.3389/fonc.2021.769730. eCollection 2021.
6
An in vivo genome-wide CRISPR screen identifies the RNA-binding protein Staufen2 as a key regulator of myeloid leukemia.体内全基因组 CRISPR 筛选发现 RNA 结合蛋白 Staufen2 是髓系白血病的关键调节因子。
Nat Cancer. 2020 Apr;1(4):410-422. doi: 10.1038/s43018-020-0054-2. Epub 2020 Apr 20.
7
Current Views on the Interplay between Tyrosine Kinases and Phosphatases in Chronic Myeloid Leukemia.慢性髓性白血病中酪氨酸激酶与磷酸酶相互作用的当前观点
Cancers (Basel). 2021 May 12;13(10):2311. doi: 10.3390/cancers13102311.
8
Dysregulation of LINC00470 and METTL3 promotes chemoresistance and suppresses autophagy of chronic myelocytic leukaemia cells.LINC00470 和 METTL3 的失调促进慢性髓性白血病细胞的化疗耐药性并抑制自噬。
J Cell Mol Med. 2021 May;25(9):4248-4259. doi: 10.1111/jcmm.16478. Epub 2021 Mar 21.
9
Development of BCR-ABL1 Transgenic Zebrafish Model Reproducing Chronic Myeloid Leukemia (CML) Like-Disease and Providing a New Insight into CML Mechanisms.BCR-ABL1 转基因斑马鱼模型的开发重现慢性髓性白血病（CML）样疾病，并为 CML 机制提供新的见解。
Cells. 2021 Feb 19;10(2):445. doi: 10.3390/cells10020445.
10
Loss of FGFR3 Delays Acute Myeloid Leukemogenesis by Programming Weakly Pathogenic CD117-Positive Leukemia Stem-Like Cells.FGFR3缺失通过对弱致病性CD117阳性白血病干细胞样细胞进行编程来延迟急性髓系白血病的发生。
Front Pharmacol. 2021 Jan 29;11:632809. doi: 10.3389/fphar.2020.632809. eCollection 2020.
本文引用的文献
1
The hematopoietic stem cell in chronic phase CML is characterized by a transcriptional profile resembling normal myeloid progenitor cells and reflecting loss of quiescence.慢性期慢性粒细胞白血病中的造血干细胞具有类似于正常髓系祖细胞的转录谱特征，并反映出静止状态的丧失。
Leukemia. 2009 May;23(5):892-9. doi: 10.1038/leu.2008.392. Epub 2009 Jan 22.
2
PTEN posttranslational inactivation and hyperactivation of the PI3K/Akt pathway sustain primary T cell leukemia viability.PTEN的翻译后失活以及PI3K/Akt信号通路的过度激活维持原发性T细胞白血病的生存能力。
J Clin Invest. 2008 Nov;118(11):3762-74. doi: 10.1172/JCI34616. Epub 2008 Oct 1.
3
The PTEN/PI3K/AKT signalling pathway in cancer, therapeutic implications.癌症中的PTEN/PI3K/AKT信号通路及其治疗意义
Curr Cancer Drug Targets. 2008 May;8(3):187-98. doi: 10.2174/156800908784293659.
4
Getting to the stem of chronic myeloid leukaemia.探寻慢性髓性白血病的根源
Nat Rev Cancer. 2008 May;8(5):341-50. doi: 10.1038/nrc2368.
5
Why is PTEN an important tumor suppressor?为什么PTEN是一种重要的肿瘤抑制因子？
J Cell Biochem. 2007 Dec 15;102(6):1368-74. doi: 10.1002/jcb.21593.
6
RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells.RAS/ERK调节人胰腺腺癌细胞中转化生长因子β（TGFβ）调控的PTEN表达。
Carcinogenesis. 2007 Nov;28(11):2321-7. doi: 10.1093/carcin/bgm159. Epub 2007 Jul 17.
7
A transforming mutation in the pleckstrin homology domain of AKT1 in cancer.癌症中AKT1的pleckstrin同源结构域的转化突变。
Nature. 2007 Jul 26;448(7152):439-44. doi: 10.1038/nature05933. Epub 2007 Jul 4.
8
PTEN is destabilized by phosphorylation on Thr366.PTEN在苏氨酸366位点发生磷酸化后会变得不稳定。
Biochem J. 2007 Aug 1;405(3):439-44. doi: 10.1042/BJ20061837.
9
Inhibition of heat shock protein 90 prolongs survival of mice with BCR-ABL-T315I-induced leukemia and suppresses leukemic stem cells.热休克蛋白90的抑制作用可延长由BCR-ABL-T315I诱导的白血病小鼠的生存期，并抑制白血病干细胞。
Blood. 2007 Jul 15;110(2):678-85. doi: 10.1182/blood-2006-10-054098. Epub 2007 Mar 29.
10
Ubiquitination regulates PTEN nuclear import and tumor suppression.泛素化调节PTEN的核输入及肿瘤抑制作用。
Cell. 2007 Jan 12;128(1):141-56. doi: 10.1016/j.cell.2006.11.040.
Zotero 插件