TYK2-STAT1-BCL2 pathway dependence in T-cell acute lymphoblastic leukemia.

Abstract

UNLABELLED:

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.

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

• Authors: Takaomi Sanda, Jeffrey W Tyner, Alejandro Gutierrez, Vu N Ngo, Jason Glover, Bill H Chang, Arla Yost, Wenxue Ma, Angela G Fleischman, Wenjun Zhou, Yandan Yang, Maria Kleppe, Yebin Ahn, Jessica Tatarek, Michelle A Kelliher, Donna S Neuberg, Ross L Levine, Richard Moriggl, Mathias Müller, Nathanael S Gray, Catriona H M Jamieson, Andrew P Weng, Louis M Staudt, Brian J Druker, A Thomas Look
• Journal: Cancer discovery (Cancer Discov) Vol. 3 Issue 5 Pg. 564-77 (May 2013) ISSN: 2159-8290 [Electronic] United States
• PMID: 23471820 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Piperidines
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins c-bcl-2
• Pyrimidines
• Pyrroles
• STAT1 Transcription Factor
• STAT1 protein, human
• Tyrphostins
• alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide
• Interleukin-10
• tofacitinib
• Janus Kinase 3
• TYK2 Kinase

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Bone Marrow Cells
• Cell Line
• Cell Survival (drug effects)
• Cells, Cultured
• Humans
• Interleukin-10 (metabolism)
• Janus Kinase 3 (antagonists & inhibitors)
• Leukocytes, Mononuclear (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Mutation
• Piperidines (pharmacology)
• Precursor T-Cell Lymphoblastic Leukemia-Lymphoma (genetics, metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• RNA Interference
• STAT1 Transcription Factor (genetics, metabolism)
• Signal Transduction
• TYK2 Kinase (antagonists & inhibitors, genetics, metabolism)
• Tyrphostins (pharmacology)