Notch pathway activation targets AML-initiating cell homeostasis and differentiation.
Notch pathway activation targets AML-initiating cell homeostasis and differentiation.
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DOI：
10.1084/jem.20121484
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发表时间：
2013-02-11
期刊：
影响因子：
--
通讯作者：
Aifantis I
中科院分区：
文献类型：
--
作者：
Lobry C;Ntziachristos P;Ndiaye-Lobry D;Oh P;Cimmino L;Zhu N;Araldi E;Hu W;Freund J;Abdel-Wahab O;Ibrahim S;Skokos D;Armstrong SA;Levine RL;Park CY;Aifantis I
Notch在AML中表现为肿瘤抑制因子，并且Notch活化诱导AML起始细胞的细胞周期停滞、分化和凋亡。已知Notch信号传导途径活化有助于一系列人类恶性肿瘤（包括T细胞白血病）的发病机制。然而，最近的研究表明Notch通路在骨髓增生性肿瘤和几种实体瘤中是一种肿瘤抑制因子。在这里，我们报告了一种新的肿瘤抑制作用的Notch信号在急性髓细胞白血病（AML），并证明Notch途径激活可能代表了这种疾病的治疗策略。我们发现Notch信号在人类AML样本中以及在该疾病的动物模型中的AML起始细胞中沉默。使用功能模型的遗传Notch获得或使用合成Notch配体的Notch信号传导的体内活化诱导AML起始细胞的快速细胞周期停滞、分化和凋亡。此外，我们证明了Notch失活与髓系肿瘤抑制因子Tet2的丢失在体内协同诱导AML样疾病。这些数据证明了Notch信号在AML中的新型肿瘤抑制作用，并阐明了Notch受体激动剂在治疗这种毁灭性白血病中的潜在治疗用途。
Notch behaves as a tumor suppressor in AML, and Notch activation induces cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Notch signaling pathway activation is known to contribute to the pathogenesis of a spectrum of human malignancies, including T cell leukemia. However, recent studies have implicated the Notch pathway as a tumor suppressor in myeloproliferative neoplasms and several solid tumors. Here we report a novel tumor suppressor role for Notch signaling in acute myeloid leukemia (AML) and demonstrate that Notch pathway activation could represent a therapeutic strategy in this disease. We show that Notch signaling is silenced in human AML samples, as well as in AML-initiating cells in an animal model of the disease. In vivo activation of Notch signaling using genetic Notch gain of function models or in vitro using synthetic Notch ligand induces rapid cell cycle arrest, differentiation, and apoptosis of AML-initiating cells. Moreover, we demonstrate that Notch inactivation cooperates in vivo with loss of the myeloid tumor suppressor Tet2 to induce AML-like disease. These data demonstrate a novel tumor suppressor role for Notch signaling in AML and elucidate the potential therapeutic use of Notch receptor agonists in the treatment of this devastating leukemia.
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影响因子：
120.7
作者：
Gentles, Andrew J.;Plevritis, Sylvia K.;Majeti, Ravindra;Alizadeh, Ash A.
通讯作者：
Alizadeh, Ash A.
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
3.6
作者：
Armstrong, SA;Golub, TR;Korsmeyer, SJ
通讯作者：
Korsmeyer, SJ
影响因子：
4.4
作者：
de Pooter, Renee F.;Schmitt, Thomas M.;Zuniga-Pflucker, Juan Carlos
通讯作者：
Zuniga-Pflucker, Juan Carlos
影响因子：
2.1
作者：
Irizarry, RA;Hobbs, B;Speed, TP
通讯作者：
Speed, TP