PI3Kγ/δ and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature.
PI3Kγ/δ and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature.
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DOI：
10.1158/1535-7163.mct-17-0141
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发表时间：
2017-10
影响因子：
5.7
通讯作者：
Diacovo TG
中科院分区：
文献类型：
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作者：
Efimenko E;Davé UP;Lebedeva IV;Shen Y;Sanchez-Quintero MJ;Diolaiti D;Kung A;Lannutti BJ;Chen J;Realubit R;Niatsetskaya Z;Ten V;Karan C;Chen X;Califano A;Diacovo TG
PI3K/AKT和NOTCH1信号通路在T细胞急性淋巴细胞白血病（T-ALL）中经常出现失调。尽管我们已表明，I类PI3K亚型p110γ和p110δ的联合活性在PTEN缺失型T-ALL的发生和进展中起主要作用，但它们对白血病发生编程的作用是否与NOTCH1激活相关的作用不同，仍有待确定。我们利用Lmo2驱动的T-ALL小鼠模型，其中PI3K/AKT和NOTCH1通路均异常上调，现已证明PI3Kγ/δ的联合活性在产生T-ALL疾病特征和促进肿瘤细胞生长方面，与NOTCH1既有重叠又有不同的作用。用PI3Kγ/δ双重抑制剂或γ-分泌酶抑制剂（GSI）治疗患病动物，可减轻肿瘤负荷、延长生存期并诱导促凋亡通路。与它们相似的生物学效应一致，在基因集富集分析中，两种抑制剂均下调了参与cMYC依赖性代谢的基因。此外，在小鼠或T-ALL细胞系中过表达cMYC可使细胞对这两种抑制剂产生抗性，这表明存在一个通路汇聚点。值得注意的是，对转录调节因子的研究和线粒体功能分析表明，PI3Kγ/δ活性在支持疾病特征和关键生物能量通路方面发挥了更大作用。研究结果为深入了解T-ALL致癌网络之间的相互关系，以及在NOTCH1和cMYC信号传导背景下PI3Kγ/δ双重抑制的治疗效果提供了思路。
PI3K/AKT and NOTCH1 signaling pathways are frequently dysregulated in T-cell acute lymphoblastic leukemias (T-ALL). Although we have shown that the combined activities of the class I PI3K isoforms p110γ and p110δ play a major role in the development and progression of PTEN null T-ALL, it has yet to be determined whether their contribution to leukemogenic programing is unique from that associated with NOTCH1 activation. Using a Lmo2-driven mouse model of T-ALL in which both the PI3K/AKT and NOTCH1 pathways are aberrantly upregulated, we now demonstrate that the combined activities of PI3Kγ/δ have both overlapping and distinct roles from NOTCH1 in generating T-ALL disease signature and in promoting tumor cell growth. Treatment of diseased animals with either a dual PI3Kγ/δ or a γ-secretase inhibitor (GSI) reduced tumor burden, prolonged survival, and induced proapoptotic pathways. Consistent with their similar biological effects, both inhibitors downregulated genes involved in cMYC-dependent metabolism in gene set enrichment analyses. Furthermore, overexpression of cMYC in mice or T-ALL cell lines conferred resistance to both inhibitors, suggesting a point of pathway convergence. Of note, interrogation of transcriptional regulators and analysis of mitochondrial function showed that PI3Kγ/δ activity played a greater role in supporting the disease signature and critical bioenergetic pathways. Results provide insight into the interrelationship between T-ALL oncogenic networks and the therapeutic efficacy of dual PI3Kγ/δ inhibition in the context of NOTCH1 and cMYC signaling.