Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia.
Mutant JAK3 phosphoproteomic profiling predicts synergism between JAK3 inhibitors and MEK/BCL2 inhibitors for the treatment of T-cell acute lymphoblastic leukemia.
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DOI：
10.1038/leu.2017.276
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发表时间：
2018-03
期刊：
影响因子：
11.4
通讯作者：
Dun MD
中科院分区：
文献类型：
--
作者：
Degryse S;de Bock CE;Demeyer S;Govaerts I;Bornschein S;Verbeke D;Jacobs K;Binos S;Skerrett-Byrne DA;Murray HC;Verrills NM;Van Vlierberghe P;Cools J;Dun MD
白细胞介素7受体(IL7R)或Janus kinase3(JAK3)的突变在T细胞急性淋巴细胞白血病(T-ALL)中频繁发生，两者都能够在小鼠模型中驱动T-ALL的细胞转化和发展。然而，JAK3突变下游的信号转导通路仍然没有得到很好的描述。在这里，我们描述了JAK3(L857Q)/(M511I)下游的磷酸蛋白质组激活转化的BA/F3淋巴细胞的突变。在JAK激酶抑制剂ruxolitinib或tofacitinib急性抑制JAK1/JAK3后，对JAK3突变体调节的信号通路进行了评估。利用磷酸蛋白质组特征进行的综合网络查询发现，调控细胞周期、翻译启动、丝裂原激活蛋白激酶和磷脂酰肌醇-4，5-二磷酸3-激酶(PI3K)/AKT信号的通路、RNA代谢以及表观遗传和凋亡过程都发生了显著变化。在JAK抑制后显示磷酸化改变的信号通路中的关键调控蛋白被selumetinib和Trametinib(MEK)、Buparlisib(PI3K)和ABT-199(BCL2)靶向，并发现在携带JAK3突变的初级T-ALL样本中与JAK激酶抑制剂联合使用具有协同作用。这些数据首次提供了JAK3突变调控的下游信号通路的详细分子特征，并进一步了解了结构性激酶激活调控的致癌过程，有助于开发改进的联合治疗方案。
Mutations in the interleukin-7 receptor (IL7R) or the Janus kinase 3 (JAK3) kinase occur frequently in T-cell acute lymphoblastic leukemia (T-ALL) and both are able to drive cellular transformation and the development of T-ALL in mouse models. However, the signal transduction pathways downstream of JAK3 mutations remain poorly characterized. Here we describe the phosphoproteome downstream of the JAK3(L857Q)/(M511I) activating mutations in transformed Ba/F3 lymphocyte cells. Signaling pathways regulated by JAK3 mutants were assessed following acute inhibition of JAK1/JAK3 using the JAK kinase inhibitors ruxolitinib or tofacitinib. Comprehensive network interrogation using the phosphoproteomic signatures identified significant changes in pathways regulating cell cycle, translation initiation, mitogen-activated protein kinase and phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/AKT signaling, RNA metabolism, as well as epigenetic and apoptotic processes. Key regulatory proteins within pathways that showed altered phosphorylation following JAK inhibition were targeted using selumetinib and trametinib (MEK), buparlisib (PI3K) and ABT-199 (BCL2), and found to be synergistic in combination with JAK kinase inhibitors in primary T-ALL samples harboring JAK3 mutations. These data provide the first detailed molecular characterization of the downstream signaling pathways regulated by JAK3 mutations and provide further understanding into the oncogenic processes regulated by constitutive kinase activation aiding in the development of improved combinatorial treatment regimens.
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DOI：
10.1083/jcb.93.1.97
发表时间：
1982-04
期刊：
The Journal of cell biology
影响因子：
--
作者：
Fujiki Y;Hubbard AL;Fowler S;Lazarow PB
通讯作者：
Lazarow PB
影响因子：
20.3
作者：
Girardi T;Vicente C;Cools J;De Keersmaecker K
通讯作者：
De Keersmaecker K
影响因子：
30.8
作者：
De Keersmaecker K;Atak ZK;Li N;Vicente C;Patchett S;Girardi T;Gianfelici V;Geerdens E;Clappier E;Porcu M;Lahortiga I;Lucà R;Yan J;Hulselmans G;Vranckx H;Vandepoel R;Sweron B;Jacobs K;Mentens N;Wlodarska I;Cauwelier B;Cloos J;Soulier J;Uyttebroeck A;Bagni C;Hassan BA;Vandenberghe P;Johnson AW;Aerts S;Cools J
通讯作者：
Cools J
影响因子：
11.4
作者：
Canté-Barrett K;Spijkers-Hagelstein JA;Buijs-Gladdines JG;Uitdehaag JC;Smits WK;van der Zwet J;Buijsman RC;Zaman GJ;Pieters R;Meijerink JP
通讯作者：
Meijerink JP
影响因子：
20.3
作者：
Degryse, Sandrine;de Bock, Charles E.;Cools, Jan
通讯作者：
Cools, Jan