TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
Department of Cancer Biology
Leukemia, Biphenotypic, Acute; TYK2 Kinase; STAT1 Transcription Factor; Proto-Oncogene Proteins c-bcl-2
Cancer Biology | Neoplasms | Oncology
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.
DOI of Published Version
Cancer Discov. 2013 May;3(5):564-577. Epub 2013 Mar 7. Link to article on publisher's site
Takaomi, Sanda; Tyner, Jeffrey W.; Gutierrez, Alejandro; Ngo, Vu N.; Glover, Jason; Chang, Bill H.; Yost, Arla; Ma, Wenxue; Fleischman, Angela G.; Zhou, Wenjun; Yang, Yandan; Kleppe, Maria; Ahn, Yebin; Tatarek, Jessica; Kelliher, Michelle A.; Neuberg, Donna S.; Levine, Ross L.; Moriggl, Richard; Muller, Mathias; Gray, Nathanael S.; Jamieson, Catriona H. M.; Weng, Andrew P.; Staudt, Louis M.; Druker, Brian J.; and Look, A. Thomas, "TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia" (2013). University of Massachusetts Medical School Faculty Publications. 40.