TYK2–STAT1–BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia

Cancer Discovery - Tập 3 Số 5 - Trang 564-577 - 2013
Takaomi Sanda1, Jeffrey W. Tyner1, Alejandro Gutiérrez1, Vu N. Ngo1, Jason Glover1, Bill H. Chang1, Arla Yost1, Wenxue Ma1, Angela G. Fleischman1, Wenjun Zhou1, Yandan Yang1, Maria Kleppe1, Yebin Ahn1, Jessica Tatarek1, Michelle A. Kelliher1, Donna Neuberg1, Ross L. Levine1, Richard Moriggl1, Mathias Müller1, Nathanael S. Gray1, Catriona Jamieson1, Andrew P. Weng1, Louis M. Staudt1, Brian J. Druker1, A. Thomas Look1
1Authors' Affiliations: Departments of 1Pediatric Oncology, 2Cancer Biology, and 3Biostatistics and Computational Biology, Dana-Farber Cancer Institute; 4Division of Hematology/Oncology, Children's Hospital Boston, Boston; and 5Department of Cancer Biology, University of Massachusetts Medical School, Worcester, Massachusetts; 6Division of Hematology and Medical Oncology, Knight Cancer Institute, and 7Division of Pediatric Hematology and Oncology, Department of Pediatrics, Oregon Health & Science University; 8Howard Hughes Medical Institute, Portland, Oregon; 9Division of Hematopoietic Stem Cell and Leukemia Research, Beckman Research Institute, City of Hope National Medical Center, Duarte; and 10Department of Medicine and Moores Cancer Center, University of California San Diego, La Jolla, California; 11Department of Pathology, Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada; 12Metabolism Branch, National Cancer Institute, Bethesda, Maryland; 13Human Oncology and Pathogenesis Progra

Tóm tắt

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. 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. Cancer Discov; 3(5); 564–77. ©2013 AACR. See related commentary by Fontan and Melnick, p. 494 This article is highlighted in the In This Issue feature, p. 471

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Cancer Discovery

Tập 3 Số 5

564-577

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