在骨髓性白血病中,AKT/FOXO信号强制执行可逆差异化阻断
Stephen M Sykes1, Steven W Lane, Lars Bullinger
1Center for Regenerative Medicine and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA.
Cell
|September 3, 2011
概括
与其他癌症相反,FOXO蛋白在急性髓性白血病 (AML) 中是活跃的. 抑制FOXO或相关途径可促进髓状细胞成熟和AML细胞死亡,从而提供新的治疗点.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 血液学 血液学 血液学
背景情况:
- 在恶性瘤中,AKT信号经常被改变,通常是通过抑制FOXO瘤抑制剂.
- 在急性髓性白血病 (AML) 中观察到AKT/FOXO信号传递的对比作用,FOXO在很大一部分患者中是活跃的.
研究的目的:
- 研究AKT/FOXO信号传导在维持急性髓性白血病 (AML) 中分化阻塞中的作用.
- 通过了解AML背后的分子机制来确定潜在的治疗点.
- 探索FOXO和JNK/c-JUN信号在AML中的相互作用.
主要方法:
- 在AML患者样本中分析FOXO活性和MLL-AF9诱导的AML的小鼠模型.
- 在白血病细胞中Akt和FoxO1/3/4的基因操纵.
- 评估白血病细胞生长,白血病发起细胞 (LIC) 功能,骨髓状细胞成熟和动物生存率.
- 在FOXO激活和JNK/c-JUN信号之间进行相关性分析.
主要成果:
- 在大约40%的AML患者样本中,FOXO蛋白是活跃的,不论基因亚型如何.
- 在小鼠模型中,Akt的激活或FoxO1/3/4的删除减少了白血病细胞的生长.
- 联合删除FoxO1/3/4显著降低了LIC功能和改善了生存率.
- 抑制FOXO诱导了骨髓质成熟和AML细胞死亡.
- FOXO激活与JNK/c-JUN信号的反相关;耐药细胞对JNK抑制作出反应.
结论:
- 积极的FOXO信号在维护AML中的差异化封锁方面发挥着至关重要的作用.
- 准FOXO或JNK/c-JUN信号可以克服这种阻塞,导致AML细胞死亡和改善结果.
- 这些发现揭示了针对AKT/FOXO和JNK/c-JUN通路的AML新治疗策略.
相关概念视频
Differentiation of Common Myeloid Progenitor Cells
Common myeloid progenitors (CMPs) are oligopotent cells that can differentiate into granulocytes and macrophages. Granulocytes and macrophages are essential for protecting the body against bacterial, viral, or fungal infections. They migrate from the bone marrow into the circulating blood to reach specific tissue sites where they differentiate and help in immune surveillance. However, they survive only for a few days and must be continuously made available to the organism to maintain a robust...
Hedgehog Signaling Pathway
The Hedgehog gene (Hh) was first discovered due to its control of the growth of disorganized, hair-like bristles phenotype in Drosophila, much like hedgehog spines. Hh plays a crucial role in the development of organs and the maintenance of homeostasis in both invertebrates and vertebrates. However, while Drosophila has only one Hh protein, mammals have multiple functional Hedgehog proteins - Sonic (Shh), Desert (Dhh), and Indian Hedgehog (Ihh). All of these homologous proteins have adapted to...
Role Of Notch Signalling In Intestinal Stem Cell Renewal
Notch signaling was first discovered in Drosophila melanogaster, where it is involved in cell lineage differentiation. Notch signaling regulates the maintenance and differentiation of intestinal stem cells or ISCs by controlling the expression of atonal homolog 1 or Atoh1. Atoh1 directs cells to differentiate into secretory cells.
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Direct cell-to-cell contact is needed for the activation of Notch signaling. The signal is initiated when a notch ligand binds to a receptor on an adjacent cell, also...
Regulation of Angiogenesis and Blood Supply
Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits. Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
Master Transcription Regulators
Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
TGF - β Signaling Pathway
The TGF-β signaling pathway regulates cell growth, differentiation, adhesion, motility, and development. TGF-β ligands that induce TGF-β signaling are synthesized in their latent form. Several proteases or cell surface receptors such as integrins act upon the latent form, releasing the active ligand. There are three types of mammalian TGF-βs: (TGF-β1, TGF-β2, and TGF-β3) that bind as homodimers or heterodimers to TGF-β receptors. The TGF-β receptors are of three kinds RI, RII, and RIII. The RI...


