title: T-cell Receptor Signaling Activates an ITK/NF-κB/GATA-3 axis in T-cell Lymphomas Facilitating Resistance to Chemotherapy.
abstract: Purpose:T-cell lymphomas are a molecularly heterogeneous group of non-Hodgkin lymphomas (NHL) that account for a disproportionate number of NHL disease-related deaths due to their inherent and acquired resistance to standard multiagent chemotherapy regimens. Despite their molecular heterogeneity and frequent loss of various T cell-specific receptors, the T-cell antigen receptor is retained in the majority of these lymphomas. As T-cell receptor (TCR) engagement activates a number of signaling pathways and transcription factors that regulate T-cell growth and survival, we examined the TCR's role in mediating resistance to chemotherapy.Experimental Design:Genetic and pharmacologic strategies were utilized to determine the contribution of tyrosine kinases and transcription factors activated in conventional T cells following TCR engagement in acquired chemotherapy resistance in primary T-cell lymphoma cells and patient-derived cell lines.Results:Here, we report that TCR signaling activates a signaling axis that includes ITK, NF-κB, and GATA-3 and promotes chemotherapy resistance.Conclusions:These observations have significant therapeutic implications, as pharmacologic inhibition of ITK prevented the activation of this signaling axis and overcame chemotherapy resistance.Clin Cancer Res; 23(10); 2506-15. ©2016 AACR.
authors: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Tianjiao
authors: T
authors: Wang
authors: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Ye
authors: Y
authors: Lu
authors: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Avery
authors: A
authors: Polk
authors: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Pinki
authors: P
authors: Chowdhury
authors: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.|Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Carlos
authors: C
authors: Murga-Zamalloa
authors: Department of Hematology, Clinical Immunology and Infectious Disease, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors: Hiroshi
authors: H
authors: Fujiwara
authors: Department of Hematology, Clinical Immunology and Infectious Disease, Graduate School of Medicine, Ehime University, Toon, Ehime, Japan.
authors: Koichiro
authors: K
authors: Suemori
authors: Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany.
authors: Niklas
authors: N
authors: Beyersdorf
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan.|Department of Dermatology, University of Michigan, Ann Arbor, Michigan.
authors: Alexandra C
authors: AC
authors: Hristov
authors: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
authors: Megan S
authors: MS
authors: Lim
authors: Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Nathanael G
authors: NG
authors: Bailey
authors: Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan. rywilcox@med.umich.edu.
authors: Ryan A
authors: RA
authors: Wilcox
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000235:genetics* / Q000276:immunology; D050990:GATA3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D016399:Lymphoma, T-Cell / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D010880:Piperidines; D061251:Primary Cell Culture; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D016328:NF-kappa B; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011948:Receptors, Antigen, T-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; C080813:emt protein-tyrosine kinase; D000225:Adenine