TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
Tyner, Jeffrey W.
Ngo, Vu N.
Chang, Bill H.
Fleischman, Angela G.
Kelliher, Michelle A.
Neuberg, Donna S.
Levine, Ross L.
Gray, Nathanael S.
Jamieson, Catriona H. M.
Weng, Andrew P.
Staudt, Louis M.
Druker, Brian J.
Look, A. Thomas
UMass Chan AffiliationsDepartment of Cancer Biology
Document TypeJournal Article
KeywordsLeukemia, Biphenotypic, Acute
STAT1 Transcription Factor
Proto-Oncogene Proteins c-bcl-2
MetadataShow full item record
AbstractTargeted 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.
SourceCancer Discov. 2013 May;3(5):564-577. Epub 2013 Mar 7. Link to article on publisher's site
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/30158
Related ResourcesLink to Article in PubMed