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 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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pediatric Oncology, Children's Hospital, Boston, MA, USA.
authors.forename: Takaomi
authors.initials: T
authors.lastname: Sanda
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.forename: Alejandro
authors.initials: A
authors.lastname: Gutierrez
authors.forename: Vu N
authors.initials: VN
authors.lastname: Ngo
authors.forename: Jason
authors.initials: J
authors.lastname: Glover
authors.forename: Bill H
authors.initials: BH
authors.lastname: Chang
authors.forename: Arla
authors.initials: A
authors.lastname: Yost
authors.forename: Wenxue
authors.initials: W
authors.lastname: Ma
authors.forename: Angela G
authors.initials: AG
authors.lastname: Fleischman
authors.forename: Wenjun
authors.initials: W
authors.lastname: Zhou
authors.forename: Yandan
authors.initials: Y
authors.lastname: Yang
authors.forename: Maria
authors.initials: M
authors.lastname: Kleppe
authors.forename: Yebin
authors.initials: Y
authors.lastname: Ahn
authors.forename: Jessica
authors.initials: J
authors.lastname: Tatarek
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Kelliher
authors.forename: Donna S
authors.initials: DS
authors.lastname: Neuberg
authors.forename: Ross L
authors.initials: RL
authors.lastname: Levine
authors.forename: Richard
authors.initials: R
authors.lastname: Moriggl
authors.forename: Mathias
authors.initials: M
authors.lastname: Müller
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.forename: Catriona H M
authors.initials: CH
authors.lastname: Jamieson
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Weng
authors.forename: Louis M
authors.initials: LM
authors.lastname: Staudt
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Druker
authors.forename: A Thomas
authors.initials: AT
authors.lastname: Look
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001854:Bone Marrow Cells; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D010880:Piperidines / Q000494:pharmacology; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D034622:RNA Interference; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011743:Pyrimidines; D011758:Pyrroles; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D016753:Interleukin-10; C479163:tofacitinib; D053616:Janus Kinase 3; D053634:TYK2 Kinase