Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells.
Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells.
复制标题
BTK和PI3Kδ的抑制损害人JMML干细胞和祖细胞的发育。
DOI：
10.1016/j.ymthe.2022.04.009
复制
发表时间：
2022-07-06
影响因子：
12.4
通讯作者：
Kapur, Reuben
中科院分区：
文献类型：
--
作者：
Ramdas, Baskar;Yuen, Lisa Deng;Palam, Lakshmi Reddy;Patel, Roshini;Pasupuleti, Santhosh Kumar;Jideonwo, Victoria;Zhang, Ji;Maguire, Callista;Wong, Eric;Kanumuri, Rahul;Zhang, Chujing;Sandusky, George;Chan, Rebecca J.;Zhang, Chi;Stieglitz, Elliot;Haneline, Laura;Kapur, Reuben
Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton’s tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment. Reuben Kapur and colleagues show that Bruton’s tyrosine kinase (BTK) is hyperphosphorylated and cooperates with p110δ, the catalytic subunit of PI3K in a JMML mouse model. JMML is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. In vivo, targeting of BTK or p110δ reduces hallmark features of JMML.
登录
查看更多内容
DOI：
10.1073/pnas.1718336115
发表时间：
2018-04-24
影响因子：
11.1
作者：
Drazic A;Aksnes H;Marie M;Boczkowska M;Varland S;Timmerman E;Foyn H;Glomnes N;Rebowski G;Impens F;Gevaert K;Dominguez R;Arnesen T
通讯作者：
Arnesen T
影响因子：
3.7
作者：
Chevaleyre J;Duchez P;Rodriguez L;Vlaski M;Villacreces A;Conrad-Lapostolle V;Praloran V;Ivanovic Z;Brunet de la Grange P
通讯作者：
Brunet de la Grange P
影响因子：
20.3
作者：
Kratz, CP;Niemeyer, CM;Loh, ML
通讯作者：
Loh, ML
影响因子：
20.3
作者：
Locatelli, F;Nöllke, P;Niemeyer, CM
通讯作者：
Niemeyer, CM
影响因子：
20.3
作者：
Bai, Ming;Grieshaber-Bouyer, Ricardo;Nigrovic, Peter A.
通讯作者：
Nigrovic, Peter A.