title: Cytokine receptor signaling is required for the survival of ALK- anaplastic large cell lymphoma, even in the presence of JAK1/STAT3 mutations.
abstract: Activating Janus kinase (JAK) and signal transducer and activator of transcription (STAT) mutations have been discovered in many T-cell malignancies, including anaplastic lymphoma kinase (ALK)-anaplastic large cell lymphomas (ALCLs). However, such mutations occur in a minority of patients. To investigate the clinical application of targeting JAK for ALK- ALCL, we treated ALK- cell lines of various histological origins with JAK inhibitors. Interestingly, most exogenous cytokine-independent cell lines responded to JAK inhibition regardless of JAK mutation status. JAK inhibitor sensitivity correlated with the STAT3 phosphorylation status of tumor cells. Using retroviral shRNA knockdown, we have demonstrated that these JAK inhibitor-sensitive cells are dependent on both JAK1 and STAT3 for survival. JAK1 and STAT3 gain-of-function mutations were found in some, but not all, JAK inhibitor-sensitive cells. Moreover, the mutations alone cannot explain the JAK1/STAT3 dependency, given that wild-type JAK1 or STAT3 was sufficient to promote cell survival in the cells that had either JAK1or STAT3 mutations. To investigate whether other mechanisms were involved, we knocked down upstream receptors GP130 or IL-2Rγ. Knockdown of GP130 or IL-2Rγ induced cell death in selected JAK inhibitor-sensitive cells. High expression levels of cytokines, including IL-6, were demonstrated in cell lines as well as in primary ALK- ALCL tumors. Finally, ruxolitinib, a JAK1/2 inhibitor, was effective in vivo in a xenograft ALK- ALCL model. Our data suggest that cytokine receptor signaling is required for tumor cell survival in diverse forms of ALK- ALCL, even in the presence of JAK1/STAT3 mutations. Therefore, JAK inhibitor therapy might benefit patients with ALK- ALCL who are phosphorylated STAT3<sup/>.
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Petrus
authors.affiliation: Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, Food and Drug Administration, Jefferson, AR 72079.
authors.forename: Wenming
authors.initials: W
authors.lastname: Xiao
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Alina
authors.initials: A
authors.lastname: Nicolae
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.affiliation: Transponics, Jacobus, PA 17407.
authors.forename: Richard N
authors.initials: RN
authors.lastname: Bamford
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Masao
authors.initials: M
authors.lastname: Nakagawa
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Sunny Tianyi
authors.initials: ST
authors.lastname: Ouyang
authors.affiliation: Pathology Department, Keck School of Medicine at University of Southern California, Los Angeles, CA 90033.
authors.forename: Alan L
authors.initials: AL
authors.lastname: Epstein
authors.affiliation: Department of Dermatology and Skin Surgery, Roger Williams Medical Center, Providence, RI 02908.
authors.forename: Marshall E
authors.initials: ME
authors.lastname: Kadin
authors.affiliation: Veneto Institute of Oncology, National Institute for Research and Treatment, 35128 Padua, Italy.
authors.forename: Annarose
authors.initials: A
authors.lastname: Del Mistro
authors.affiliation: Innovative Medicines and Early Development Oncology, AstraZeneca Pharmaceuticals, Waltham, MA 02139.
authors.forename: Richard
authors.initials: R
authors.lastname: Woessner
authors.affiliation: Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892.
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
authors.affiliation: Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892; tawald@helix.nih.gov.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Waldmann
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009570:Nitriles; D010766:Phosphorylation; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D016207:Cytokines; D009570:Nitriles; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D018121:Receptors, Cytokine; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050822:Cytokine Receptor gp130; C540383:ruxolitinib; C479163:tofacitinib; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C507904:JAK1 protein, human; D053613:Janus Kinase 1
keywords: ALK− ALCL; JAK; STAT; cytokine receptor; mutations