{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T04:30:30Z","timestamp":1791174630376,"version":"4.1.0"},"reference-count":49,"publisher":"American Association for Cancer Research (AACR)","issue":"5","content-domain":{"domain":["aacrjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2013,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>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\u2013STAT1 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\u2013STAT1\u2013BCL2 pathway for continued survival, supporting the development of molecular therapies targeting TYK2 and other components of this pathway.<\/jats:p>\n                  <jats:p>Significance: In recent years, \u201cpathway dependence\u201d 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\u201377. \u00a92013 AACR.<\/jats:p>\n                  <jats:p>See related commentary by Fontan and Melnick, p. 494<\/jats:p>\n                  <jats:p>This article is highlighted in the In This Issue feature, p. 471<\/jats:p>","DOI":"10.1158\/2159-8290.cd-12-0504","type":"journal-article","created":{"date-parts":[[2013,3,7]],"date-time":"2013-03-07T22:35:03Z","timestamp":1362695703000},"page":"564-577","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":136,"title":["TYK2\u2013STAT1\u2013BCL2 Pathway Dependence in T-cell Acute Lymphoblastic Leukemia"],"prefix":"10.1158","volume":"3","author":[{"given":"Takaomi","family":"Sanda","sequence":"first","affiliation":[{"name":"Authors' 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey W.","family":"Tyner","sequence":"additional","affiliation":[{"name":"Authors' 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Gutierrez","sequence":"additional","affiliation":[{"name":"Authors' 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"},{"name":"Authors' 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vu N.","family":"Ngo","sequence":"additional","affiliation":[{"name":"Authors' 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Glover","sequence":"additional","affiliation":[{"name":"Authors' 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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bill H.","family":"Chang","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Pediatric Oncology, 2Cancer Biology, and 3Biostatistics and Computational Biology, Dana-Farber Cancer Institute; 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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"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mathias","family":"M\u00fcller","sequence":"additional","affiliation":[{"name":"Authors' Affiliations: Departments of 1Pediatric Oncology, 2Cancer Biology, and 3Biostatistics and Computational Biology, Dana-Farber Cancer Institute; 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Thomas","family":"Look","sequence":"additional","affiliation":[{"name":"Authors' 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 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