TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia Journal Article
| Authors: | Sanda, T.; Tyner, J. W.; Gutierrez, A.; Ngo, V. N.; Glover, J.; Chang, B. H.; Yost, A.; Ma, W.; Fleischman, A. G.; Zhou, W.; Yang, Y.; Kleppe, M.; Ahn, Y.; Tatarek, J.; Kelliher, M. A.; Neuberg, D. S.; Levine, R. L.; Moriggl, R.; Müller, M.; Gray, N. S.; Jamieson, C. H. M.; Weng, A. P.; Staudt, L. M.; Druker, B. J.; Thomas Look, A. |
| Article Title: | TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia |
| 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 Janusactivated 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. Significance: In recent years, "pathway dependence" has been revealed in specific 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. © 2013 American Association for Cancer Research. |
| Keywords: | signal transduction; controlled study; protein expression; human cell; sequence analysis; mutation; nonhuman; antineoplastic agents; flow cytometry; cell proliferation; t lymphocyte; animal cell; mouse; animals; mice; animal tissue; cell viability; bone marrow cells; cell survival; cells, cultured; protein bcl 2; stat1 protein; reverse transcription polymerase chain reaction; apoptosis; gene expression; interleukin 6 receptor; cell line; animal experiment; animal model; rna interference; pyrimidines; mice, inbred c57bl; acute lymphoblastic leukemia; mice, transgenic; protein kinase inhibitors; leukocytes, mononuclear; microarray analysis; newborn; immunoblotting; protein kinase tyk2; piperidines; gene silencing; pyrroles; ic 50; loss of function mutation; transient transfection; fluorescence activated cell sorting; proto-oncogene proteins c-bcl-2; short hairpin rna; precursor t-cell lymphoblastic leukemia-lymphoma; interleukin-10; cloning; tyrphostins; janus kinase 3; interleukin 3; interleukin 10 receptor; alpha interferon receptor; stat1 transcription factor; interleukin 12 receptor; beta interferon receptor; interleukin 11 receptor; interleukin 23 receptor; tyk2 kinase |
| Journal Title: | Cancer Discovery |
| Volume: | 3 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-05-01 |
| Start Page: | 564 |
| End Page: | 577 |
| Language: | English |
| DOI: | 10.1158/2159-8290.cd-12-0504 |
| PROVIDER: | scopus |
| PMCID: | PMC3651770 |
| PUBMED: | 23471820 |
| DOI/URL: | |
| Notes: | --- - Cited By (since 1996):1 - "Export Date: 3 June 2013" - "Source: Scopus" |
