期刊
CANCER DISCOVERY
卷 3, 期 5, 页码 564-577出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-12-0504
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资金
- William Lawrence and Blanche Hughes Fund
- Leukemia & Lymphoma Society
- Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research
- National Cancer Institute [4R00CA151457-03]
- Oregon Clinical and Translational Research Institute (OCTRI) from the National Center for Research Resources (NRCC), a component of the NIH [UL1 RR024140]
- NIH Roadmap for Medical Research
- NIH [NCI 1K99CA157951, NCI 1K08CA133103]
- Children's Leukemia Research Association
- Japan Society for the Promotion of Science
- Oregon Child Health Research Center
- Austrian Science Fund FWF [SFB F28]
- NCI [5P01CA109901, NCI 5P01CA68484]
- Alex's Lemonade Stand Foundation Bridge grant
- European Molecular Biology Organization (EMBO) long-term fellowship
- CIHR/Terry Fox Foundation
- California Institute for Regenerative Medicine (CIRM) [TR21789, RN2-00910-1, DR1-01430]
- Leichtag Family Foundation
- Ratner Family Foundation
- [5P30CA069533]
Targeted molecular therapy has yielded remarkable outcomes in certain cancers, but specific therapeutic targets remain elusive for many others. As a result of two independent RNA interference (RNAi) screens, we identified pathway dependence on a member of the Janus-activated kinase (JAK) tyrosine kinase family, TYK2, and its downstream effector STAT1, in T-cell acute lymphoblastic leukemia (T-ALL). Gene knockdown experiments consistently showed TYK2 dependence in both T-ALL primary specimens and cell lines, and a small-molecule inhibitor of JAK activity induced T-ALL cell death. Activation of this TYK2-STAT1 pathway in T-ALL cell lines occurs by gain-of-function TYK2 mutations or activation of interleukin (IL)-10 receptor signaling, and this pathway mediates T-ALL cell survival through upregulation of the antiapoptotic protein BCL2. These findings indicate that in many T-ALL cases, the leukemic cells are dependent upon the TYK2-STAT1-BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway. SIGNIFICANCE: In recent years, pathway dependence has been revealed in specific types of human cancer, which can be important because they pinpoint proteins that are particularly vulnerable to antitumor-targeted inhibition (so-called Achilles' heel proteins). Here, we use RNAi technology to identify a novel oncogenic pathway that involves aberrant activation of the TYK2 tyrosine kinase and its downstream substrate, STAT1, which ultimately promotes T-ALL cell survival through the upregulation of BCL2 expression. Cancer Discov; 3(5); 564-77. (C) 2013 AACR.
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