TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia.

Cancer Discov
Publication Year: 
Takaomi Sanda , Jeffrey W Tyner , Alejandro Gutierrez , Vu N Ngo , Jason Glover , Bill H Chang , Arla Yost , Wenxue Ma , Angela G Fleischman , Wenjun Zhou , Yandan Yang , Maria Kleppe , Yebin Ahn , Jessica Tatarek , Michelle A Kelliher , Donna S Neuberg , Ross L Levine , Richard Moriggl , Mathias Muller , Nathanael S Gray , Catriona H M Jamieson , Andrew P Weng , Louis M Staudt , Brian J Druker , A Thomas Look
Public Summary: 
In recent years, “pathway dependence” has been revealed in specifi c 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. ©2013 AACR.
Scientific Abstract: 
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.

© 2013 California Institute for Regenerative Medicine