University of Massachusetts Medical School Faculty Publications
Title
TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia
UMMS Affiliation
Department of Cancer Biology
Publication Date
2013-5
Document Type
Article
Subjects
Leukemia, Biphenotypic, Acute; TYK2 Kinase; STAT1 Transcription Factor; Proto-Oncogene Proteins c-bcl-2
Disciplines
Cancer Biology | Neoplasms | Oncology
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.
DOI of Published Version
10.1158/2159-8290.CD-12-0504
Source
Cancer Discov. 2013 May;3(5):564-577. Epub 2013 Mar 7. Link to article on publisher's site
Related Resources
Journal/Book/Conference Title
Cancer discovery
PubMed ID
23471820
Repository Citation
Takaomi S, Tyner JW, Gutierrez A, Ngo VN, Glover J, Chang BH, Yost A, Ma W, Fleischman AG, Zhou W, Yang Y, Kleppe M, Ahn Y, Tatarek J, Kelliher MA, Neuberg DS, Levine RL, Moriggl R, Muller M, Gray NS, Jamieson CH, Weng AP, Staudt LM, Druker BJ, Look AT. (2013). TYK2-STAT1-BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1158/2159-8290.CD-12-0504. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/40