HIF1α 对于慢性髓性白血病干细胞的存活维持是必需的。
HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells.
机构信息
Division of Hematology/Oncology, Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
出版信息
Blood. 2012 Mar 15;119(11):2595-607. doi: 10.1182/blood-2011-10-387381. Epub 2012 Jan 24.
Abstract
Hypoxia-inducible factor-1α (HIF1α), a master transcriptional regulator of the cellular and systemic hypoxia response, is essential for the maintenance of self-renewal capacity of normal HSCs. It is still unknown whether HIF1α has a role in survival regulation of leukemia stem cells (LSCs) in chronic myeloid leukemia (CML). Using a mouse model of CML, here we report that HIF1α plays a crucial role in survival maintenance of LSCs. Deletion of HIF1α impairs the propagation of CML through impairing cell-cycle progression and inducing apoptosis of LSCs. Deletion of HIF1α results in elevated expression of p16(Ink4a) and p19(Arf) in LSCs, and knockdown of p16(Ink4a) and p19(Arf) rescues the defective colony-forming ability of HIF1α(-/-) LSCs. Compared with normal HSCs, LSCs appear to be more dependent on the HIF1α pathway. Together, these results demonstrate that HIF1α represents a critical pathway in LSCs and inhibition of the HIF1α pathway provides a therapeutic strategy for eradicating LSCs in CML.
摘要
缺氧诱导因子-1α（HIF1α）是细胞和全身缺氧反应的主要转录调节因子，对维持正常造血干细胞的自我更新能力至关重要。目前尚不清楚 HIF1α 是否在慢性髓系白血病（CML）中的白血病干细胞（LSCs）的存活调节中发挥作用。在这里，我们使用 CML 的小鼠模型报告称，HIF1α 在 LSCs 的存活维持中发挥着关键作用。HIF1α 的缺失通过损害 LSCs 的细胞周期进程和诱导其凋亡来损害 CML 的增殖。HIF1α 的缺失导致 LSCs 中 p16(Ink4a)和 p19(Arf)的表达升高，而敲低 p16(Ink4a)和 p19(Arf)则挽救了 HIF1α(-/-)LSCs 缺陷的集落形成能力。与正常造血干细胞相比，LSCs 似乎更依赖于 HIF1α 途径。总之，这些结果表明 HIF1α 是 LSCs 中的关键途径，抑制 HIF1α 途径为消除 CML 中的 LSCs 提供了一种治疗策略。
相似文献
1
HIF1α is required for survival maintenance of chronic myeloid leukemia stem cells.HIF1α 对于慢性髓性白血病干细胞的存活维持是必需的。
Blood. 2012 Mar 15;119(11):2595-607. doi: 10.1182/blood-2011-10-387381. Epub 2012 Jan 24.
2
Microenvironmental protection of CML stem and progenitor cells from tyrosine kinase inhibitors through N-cadherin and Wnt-β-catenin signaling.通过 N-钙黏蛋白和 Wnt-β-连环蛋白信号转导对慢性髓性白血病干细胞和祖细胞进行微环境保护，免受酪氨酸激酶抑制剂的影响。
Blood. 2013 Mar 7;121(10):1824-38. doi: 10.1182/blood-2012-02-412890. Epub 2013 Jan 8.
3
YBX1 regulates the survival of chronic myeloid leukemia stem cells by modulating mA-mediated YWHAZ stability.YBX1通过调节m⁶A介导的YWHAZ稳定性来调控慢性髓性白血病干细胞的存活。
Cell Oncol (Dordr). 2023 Apr;46(2):451-464. doi: 10.1007/s13402-022-00762-w. Epub 2022 Dec 13.
4
CD150(-) Side Population Defines Leukemia Stem Cells in a BALB/c Mouse Model of CML and Is Depleted by Genetic Loss of SIRT1.CD150（-）侧群细胞在BALB/c小鼠慢性粒细胞白血病模型中定义白血病干细胞，并因SIRT1基因缺失而减少。
Stem Cells. 2015 Dec;33(12):3437-51. doi: 10.1002/stem.2218. Epub 2015 Oct 15.
5
Bone marrow niche trafficking of miR-126 controls the self-renewal of leukemia stem cells in chronic myelogenous leukemia.骨髓龛中小分子 RNA-126 的转移调控慢性髓系白血病中白血病干细胞的自我更新。
Nat Med. 2018 May;24(4):450-462. doi: 10.1038/nm.4499. Epub 2018 Mar 5.
6
Anthelmintic Niclosamide Disrupts the Interplay of p65 and FOXM1/β-catenin and Eradicates Leukemia Stem Cells in Chronic Myelogenous Leukemia.抗蠕虫药尼氯硝唑破坏 p65 和 FOXM1/β-连环蛋白的相互作用并根除慢性髓性白血病中的白血病干细胞。
Clin Cancer Res. 2017 Feb 1;23(3):789-803. doi: 10.1158/1078-0432.CCR-16-0226. Epub 2016 Aug 4.
7
LIGHT/LTβR signaling regulates self-renewal and differentiation of hematopoietic and leukemia stem cells.LIGHT/LTβR 信号通路调节造血干/祖细胞和白血病干细胞的自我更新和分化。
Nat Commun. 2021 Feb 16;12(1):1065. doi: 10.1038/s41467-021-21317-x.
8
A tumor suppressor function of the Msr1 gene in leukemia stem cells of chronic myeloid leukemia.Msr1 基因在慢性髓性白血病白血病干细胞中的肿瘤抑制功能。
Blood. 2011 Jul 14;118(2):390-400. doi: 10.1182/blood-2010-11-316760. Epub 2011 May 19.
9
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.
10
Physiologic hypoxia promotes maintenance of CML stem cells despite effective BCR-ABL1 inhibition.生理性缺氧可促进 CML 干细胞的维持，尽管 BCR-ABL1 受到有效抑制。
Blood. 2014 May 22;123(21):3316-26. doi: 10.1182/blood-2013-07-511907. Epub 2014 Apr 4.
引用本文的文献
1
Methylglyoxal Formation-Metabolic Routes and Consequences.甲基乙二醛的形成——代谢途径及后果
Antioxidants (Basel). 2025 Feb 13;14(2):212. doi: 10.3390/antiox14020212.
2
Long-term adaptation of lymphoma cell lines to hypoxia is mediated by diverse molecular mechanisms that are targetable with specific inhibitors.淋巴瘤细胞系对缺氧的长期适应是由多种分子机制介导的，这些机制可用特定抑制剂靶向作用。
Cell Death Discov. 2025 Feb 18;11(1):65. doi: 10.1038/s41420-025-02341-y.
3
3D human stem-cell-derived neuronal spheroids for neurotoxicity testing of methylglyoxal, highly reactive glycolysis byproduct and potent glycating agent.用于甲基乙二醛神经毒性测试的3D人干细胞衍生神经球，甲基乙二醛是一种高反应性糖酵解副产物和强效糖化剂。
Curr Res Toxicol. 2024 Jun 9;7:100176. doi: 10.1016/j.crtox.2024.100176. eCollection 2024.
4
Accumulation of Non-Pathological Liver Fat Is Associated with the Loss of Glyoxalase I Activity in Humans.非病理性肝脂肪堆积与人类乙二醛酶I活性丧失有关。
Metabolites. 2024 Apr 7;14(4):209. doi: 10.3390/metabo14040209.
5
Integrative single-cell expression and functional studies unravels a sensitization to cytarabine-based chemotherapy through HIF pathway inhibition in AML leukemia stem cells.整合单细胞表达和功能研究揭示了通过抑制AML白血病干细胞中的HIF通路对阿糖胞苷化疗的敏感性。
Hemasphere. 2024 Feb 26;8(2):e45. doi: 10.1002/hem3.45. eCollection 2024 Feb.
6
HIF-1 regulates pathogenic cytotoxic T cells in lupus skin disease.缺氧诱导因子 1 调控狼疮皮肤病中的致病细胞毒性 T 细胞。
JCI Insight. 2023 Aug 22;8(16):e166076. doi: 10.1172/jci.insight.166076.
7
Metabolic adaptation to tyrosine kinase inhibition in leukemia stem cells.白血病干细胞中酪氨酸激酶抑制的代谢适应。
Blood. 2023 Aug 10;142(6):574-588. doi: 10.1182/blood.2022018196.
8
Metabolic crosstalk between stromal and malignant cells in the bone marrow niche.骨髓微环境中基质细胞与恶性细胞之间的代谢串扰。
Bone Rep. 2023 Feb 27;18:101669. doi: 10.1016/j.bonr.2023.101669. eCollection 2023 Jun.
9
The Bone Marrow Immune Microenvironment in CML: Treatment Responses, Treatment-Free Remission, and Therapeutic Vulnerabilities.慢性髓性白血病中的骨髓免疫微环境：治疗反应、无治疗缓解和治疗弱点。
Curr Hematol Malig Rep. 2023 Apr;18(2):19-32. doi: 10.1007/s11899-023-00688-6. Epub 2023 Feb 13.
10
YBX1 regulates the survival of chronic myeloid leukemia stem cells by modulating mA-mediated YWHAZ stability.YBX1通过调节m⁶A介导的YWHAZ稳定性来调控慢性髓性白血病干细胞的存活。
Cell Oncol (Dordr). 2023 Apr;46(2):451-464. doi: 10.1007/s13402-022-00762-w. Epub 2022 Dec 13.
本文引用的文献
1
Targeting HIF1α eliminates cancer stem cells in hematological malignancies.靶向 HIF1α 可消除血液系统恶性肿瘤中的癌症干细胞。
Cell Stem Cell. 2011 Apr 8;8(4):399-411. doi: 10.1016/j.stem.2011.02.006.
2
HIF-1α depletion results in SP1-mediated cell cycle disruption and alters the cellular response to chemotherapeutic drugs.HIF-1α 耗竭导致 SP1 介导的细胞周期紊乱，并改变细胞对化疗药物的反应。
Cell Cycle. 2011 Apr 15;10(8):1249-60. doi: 10.4161/cc.10.8.15326.
3
Hypoxia-inducible factors and the response to hypoxic stress.缺氧诱导因子与应对缺氧应激。
Mol Cell. 2010 Oct 22;40(2):294-309. doi: 10.1016/j.molcel.2010.09.022.
4
Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.HIF-1alpha 水平的调节对造血干细胞至关重要。
Cell Stem Cell. 2010 Sep 3;7(3):391-402. doi: 10.1016/j.stem.2010.06.020.
5
Oxygen in stem cell biology: a critical component of the stem cell niche.干细胞生物学中的氧气：干细胞生态位的关键组成部分。
Cell Stem Cell. 2010 Aug 6;7(2):150-61. doi: 10.1016/j.stem.2010.07.007.
6
Knock down of HIF-1alpha in glioma cells reduces migration in vitro and invasion in vivo and impairs their ability to form tumor spheres.敲低胶质瘤细胞中的 HIF-1alpha 可减少体外迁移和体内侵袭，并损害其形成肿瘤球的能力。
Mol Cancer. 2010 Jun 1;9:133. doi: 10.1186/1476-4598-9-133.
7
Linking functional decline of telomeres, mitochondria and stem cells during ageing.衰老过程中端粒、线粒体和干细胞功能下降的关联。
Nature. 2010 Mar 25;464(7288):520-8. doi: 10.1038/nature08982.
8
Hypoxia mediates low cell-cycle activity and increases the proportion of long-term-reconstituting hematopoietic stem cells during in vitro culture.缺氧在体外培养过程中调节低细胞周期活性，并增加长期重建造血干细胞的比例。
Exp Hematol. 2010 Apr;38(4):301-310.e2. doi: 10.1016/j.exphem.2010.01.005. Epub 2010 Feb 4.
9
Senescence in tumours: evidence from mice and humans.肿瘤衰老：来自小鼠和人类的证据。
Nat Rev Cancer. 2010 Jan;10(1):51-7. doi: 10.1038/nrc2772.
10
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.
Zotero 插件