High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia
High selective pressure for Notch1 mutations that induce Myc in T-cell acute lymphoblastic leukemia
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DOI：
10.1182/blood-2016-01-692855
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发表时间：
2016-11-03
期刊：
影响因子：
20.3
通讯作者：
Pear, Warren S.
中科院分区：
文献类型：
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作者：
Chiang, Mark Y.;Wang, Qing;Pear, Warren S.
激活NOTCH 1突变在人类T细胞急性淋巴细胞白血病（T-ALL）中很常见，Notch抑制剂（g-分泌酶抑制剂[GSI]）已在复发性、难治性疾病患者中产生应答。然而，持续的反应，虽然报告，是罕见的，这表明其他途径可以替代Notch在T-ALL。为了解决这种可能性，我们首先产生了Kras（G12 D）转基因小鼠，其T细胞特异性表达泛Notch抑制剂，显性阴性Mastermind（DNMAML）。这些小鼠患上了白血病，但肿瘤细胞没有进入替代致癌途径，而是获得了Notch 1突变，随后删除了DNMAML，这强化了活化的Notch 1在T细胞祖细胞中特别具有转化作用的观点。我们接下来采取了一种候选方法来鉴定Notch下游的致癌途径，重点是Myc和Akt，它们是T细胞祖细胞中的Notch靶点。用Myc转导的Kras（G12 D）小鼠产生了GSI不敏感且缺乏Notch 1突变的T-ALL。相比之下，用豆蔻酰化AKT转导的Kras（G12 D）小鼠产生获得Notch 1突变的GSI敏感性T-ALL。因此，Myc可以在白血病发生中取代Notch 1，而Akt不能。原发性肿瘤中的这些发现扩展了最近使用人T-ALL细胞系和异种移植物的工作，并表明Notch/Myc信号传导轴在理解T-ALL中Notch突变的选择性压力以及T-ALL对Notch通路抑制剂的反应和抗性方面具有重要意义。
Activating NOTCH1 mutations are frequent in human T-cell acute lymphoblastic leukemia (T-ALL) and Notch inhibitors (g-secretase inhibitors [GSIs]) have produced responses in patients with relapsed, refractory disease. However, sustained responses, although reported, are uncommon, suggesting that other pathways can substitute for Notch in T-ALL. To address this possibility, we first generated Kras(G12D) transgenic mice with T-cell-specific expression of the pan-Notch inhibitor, dominant-negative Mastermind (DNMAML). These mice developed leukemia, but instead of accessing alternative oncogenic pathways, the tumor cells acquired Notch1 mutations and subsequently deleted DNMAML, reinforcing the notion that activated Notch1 is particularly transforming within the context of T-cell progenitors. We next took a candidate approach to identify oncogenic pathways downstream of Notch, focusing on Myc and Akt, which are Notch targets in T-cell progenitors. Kras(G12D) mice transduced with Myc developed T-ALLs that were GSI-insensitive and lacked Notch1 mutations. In contrast, Kras(G12D) mice transduced with myristoylated AKT developed GSI-sensitive T-ALLs that acquired Notch1 mutations. Thus, Myc can substitute for Notch1 in leukemogenesis, whereas Akt cannot. These findings in primary tumors extend recent work using human T-ALL cell lines and xenografts and suggest that the Notch/Myc signaling axis is of predominant importance in understanding both the selective pressure for Notch mutations in T-ALL and response and resistance of T-ALL to Notch pathway inhibitors.