TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
dc.contributor.author | Takaomi, Sanda | |
dc.contributor.author | Tyner, Jeffrey W. | |
dc.contributor.author | Gutierrez, Alejandro | |
dc.contributor.author | Ngo, Vu N. | |
dc.contributor.author | Glover, Jason | |
dc.contributor.author | Chang, Bill H. | |
dc.contributor.author | Yost, Arla | |
dc.contributor.author | Ma, Wenxue | |
dc.contributor.author | Fleischman, Angela G. | |
dc.contributor.author | Zhou, Wenjun | |
dc.contributor.author | Yang, Yandan | |
dc.contributor.author | Kleppe, Maria | |
dc.contributor.author | Ahn, Yebin | |
dc.contributor.author | Tatarek, Jessica | |
dc.contributor.author | Kelliher, Michelle A. | |
dc.contributor.author | Neuberg, Donna S. | |
dc.contributor.author | Levine, Ross L. | |
dc.contributor.author | Moriggl, Richard | |
dc.contributor.author | Muller, Mathias | |
dc.contributor.author | Gray, Nathanael S. | |
dc.contributor.author | Jamieson, Catriona H. M. | |
dc.contributor.author | Weng, Andrew P. | |
dc.contributor.author | Staudt, Louis M. | |
dc.contributor.author | Druker, Brian J. | |
dc.contributor.author | Look, A. Thomas | |
dc.date | 2022-08-11T08:08:30.000 | |
dc.date.accessioned | 2022-08-23T15:57:16Z | |
dc.date.available | 2022-08-23T15:57:16Z | |
dc.date.issued | 2013-05-01 | |
dc.date.submitted | 2013-06-18 | |
dc.identifier.citation | Cancer Discov. 2013 May;3(5):564-577. Epub 2013 Mar 7. <a href="http://dx.doi.org/10.1158/2159-8290.CD-12-0504">Link to article on publisher's site</a> | |
dc.identifier.issn | 2159-8274 (Linking) | |
dc.identifier.doi | 10.1158/2159-8290.CD-12-0504 | |
dc.identifier.pmid | 23471820 | |
dc.identifier.uri | http://hdl.handle.net/20.500.14038/30158 | |
dc.description.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. | |
dc.language.iso | en_US | |
dc.relation | <a href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Retrieve&list_uids=23471820&dopt=Abstract">Link to Article in PubMed</a> | |
dc.relation.url | http://dx.doi.org/10.1158/2159-8290.CD-12-0504 | |
dc.subject | Leukemia, Biphenotypic, Acute | |
dc.subject | TYK2 Kinase | |
dc.subject | STAT1 Transcription Factor | |
dc.subject | Proto-Oncogene Proteins c-bcl-2 | |
dc.subject | Cancer Biology | |
dc.subject | Neoplasms | |
dc.subject | Oncology | |
dc.title | TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia | |
dc.type | Journal Article | |
dc.source.journaltitle | Cancer discovery | |
dc.source.volume | 3 | |
dc.source.issue | 5 | |
dc.identifier.legacycoverpage | https://escholarship.umassmed.edu/faculty_pubs/40 | |
dc.identifier.contextkey | 4236671 | |
html.description.abstract | <p>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.</p> | |
dc.identifier.submissionpath | faculty_pubs/40 | |
dc.contributor.department | Department of Cancer Biology | |
dc.source.pages | 564-577 |