Notch activation inhibits AML growth and survival: a potential therapeutic approach.
Notch activation inhibits AML growth and survival: a potential therapeutic approach.
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DOI：
10.1084/jem.20121527
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发表时间：
2013-02-11
期刊：
影响因子：
--
通讯作者：
Zweidler-McKay PA
中科院分区：
文献类型：
--
作者：
Kannan S;Sutphin RM;Hall MG;Golfman LS;Fang W;Nolo RM;Akers LJ;Hammitt RA;McMurray JS;Kornblau SM;Melnick AM;Figueroa ME;Zweidler-McKay PA
用Notch激动肽激活Notch可诱导AML患者样本中的细胞凋亡。虽然Notch的异常激活有助于T细胞的白血病发生，但其在急性髓细胞白血病(AML)中的作用尚不清楚。在这里，我们报告了人AML样本中Notch受体的强烈表达；然而，Notch受体激活和下游Notch靶标的表达非常低，这表明Notch在人AML中存在，但不是结构性激活的。这些Notch受体在AML中的功能作用尚不清楚。通过任何Notch受体(Notch1-4)或通过Notch靶向毛发/增强子1(HES1)诱导的激活，持续地导致AML生长停滞和caspase依赖的细胞凋亡，这与B细胞淋巴瘤2(BCL2)缺失和p53/p21表达增强有关。这些作用依赖于HES1抑制因子结构域，并通过bcl2的重新表达而被挽救。重要的是，激活的Notch1、Notch2和HES1在体内都能抑制AML的生长，而通过dnMAML抑制Notch可以促进体内的增殖，从而揭示了Notch信号对AML体内生长的生理抑制作用。作为一种新的治疗方法，我们使用了一种Notch激动肽，它导致AML患者样本中显著的细胞凋亡。综上所述，我们报道了在人类AML中Notch介导的一致的生长抑制和凋亡，并建议开发Notch激动剂作为AML的潜在治疗方法。
Activating Notch with a Notch agonist peptide induces apoptosis in AML patient samples. Although aberrant Notch activation contributes to leukemogenesis in T cells, its role in acute myelogenous leukemia (AML) remains unclear. Here, we report that human AML samples have robust expression of Notch receptors; however, Notch receptor activation and expression of downstream Notch targets are remarkably low, suggesting that Notch is present but not constitutively activated in human AML. The functional role of these Notch receptors in AML is not known. Induced activation through any of the Notch receptors (Notch1–4), or through the Notch target Hairy/Enhancer of Split 1 (HES1), consistently leads to AML growth arrest and caspase-dependent apoptosis, which are associated with B cell lymphoma 2 (BCL2) loss and enhanced p53/p21 expression. These effects were dependent on the HES1 repressor domain and were rescued through reexpression of BCL2. Importantly, activated Notch1, Notch2, and HES1 all led to inhibited AML growth in vivo, and Notch inhibition via dnMAML enhanced proliferation in vivo, thus revealing the physiological inhibition of AML growth in vivo in response to Notch signaling. As a novel therapeutic approach, we used a Notch agonist peptide that led to significant apoptosis in AML patient samples. In conclusion, we report consistent Notch-mediated growth arrest and apoptosis in human AML, and propose the development of Notch agonists as a potential therapeutic approach in AML.
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DOI：
10.1007/978-1-61779-286-1_10
发表时间：
2011
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Kornblau SM;Coombes KR
通讯作者：
Coombes KR
影响因子：
45.3
作者：
Jerez, Andres;Gondek, Lukasz P.;Maciejewski, Jaroslaw P.
通讯作者：
Maciejewski, Jaroslaw P.
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
20.3
作者：
Carlesso, N;Aster, JC;Scadden, DT
通讯作者：
Scadden, DT
影响因子：
2.3
作者：
Chadwick, Nicholas;Fennessy, Carl;Buckle, Anne-Marie
通讯作者：
Buckle, Anne-Marie