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ITK-Syk from Deregulated Lymphocyte Activation by Premature Terminal

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ITK-Syk from Deregulated Lymphocyte Activation by Premature Terminal Premature Terminal Differentiation Protects from Deregulated Lymphocyte Activation by ITK-Syk This information is current as Martina P. Bach, Eva Hug, Markus Werner, Julian Holch, of September 28, 2021. Clara Sprissler, Konstanze Pechloff, Katja Zirlik, Robert Zeiser, Christine Dierks, Jürgen Ruland and Hassan Jumaa J Immunol 2014; 192:1024-1033; Prepublished online 27 December 2013; doi: 10.4049/jimmunol.1300420 Downloaded from http://www.jimmunol.org/content/192/3/1024 Supplementary http://www.jimmunol.org/content/suppl/2013/12/26/jimmunol.130042 Material 0.DCSupplemental http://www.jimmunol.org/ References This article cites 55 articles, 21 of which you can access for free at: http://www.jimmunol.org/content/192/3/1024.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 28, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Premature Terminal Differentiation Protects from Deregulated Lymphocyte Activation by ITK-Syk Martina P. Bach,*,† Eva Hug,† Markus Werner,*,† Julian Holch,‡ Clara Sprissler,x Konstanze Pechloff,‡,{ Katja Zirlik,x Robert Zeiser,x Christine Dierks,x Ju¨rgen Ruland,‡,{ and Hassan Jumaa*,† The development of hematopoietic neoplasms is often associated with mutations, altered gene expression or chromosomal trans- locations. Recently, the t(5, 9)(q33;q22) translocation was found in a subset of peripheral T cell lymphomas and was shown to result in an IL-2–inducible kinase–spleen tyrosine kinase (ITK-Syk) fusion transcript. In this study, we show that T cell–specific expression of the ITK-Syk oncogene in mice leads to an early onset and aggressive polyclonal T cell lymphoproliferation with concomitant B cell expansion and systemic inflammation by 7–9 wk of age. Because this phenotype is strikingly different from previous work showing that ITK-Syk expression causes clonal T cell lymphoma by 20–27 wk of age, we investigated the underlying Downloaded from molecular mechanism in more detail. We show that the reason for the severe phenotype is the lack of B-lymphocyte–induced maturation protein-1 (Blimp-1) induction by low ITK-Syk expression. In contrast, high ITK-Syk oncogene expression induces terminal T cell differentiation in the thymus by activating Blimp-1, thereby leading to elimination of oncogene-expressing cells early in development. Our data suggest that terminal differentiation is an important mechanism to prevent oncogene-expressing cells from malignant transformation, as high ITK-Syk oncogene activity induces cell elimination. Accordingly, for transformation, a specific amount of oncogene is required, or alternatively, the induction of terminal differentiation is defective. The Journal of http://www.jimmunol.org/ Immunology, 2014, 192: 1024–1033. pleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase phocytic leukemia and diffuse large B cell lymphoma cells, in- that possesses two N-terminal Src homology 2 domains and dicating that Syk is crucial for the survival of these cells (7, 8). S a C-terminal kinase domain. Syk is widely expressed in Syk has also been linked to malignancies of other hematopoietic all hematopoietic cells, mediates various biological functions, and lineages such as peripheral T cell lymphomas (PTCLs), in which plays a central role in B cell development and signal transduction Syk is overexpressed in .90% of all PTCLs (9). downstream of the BCR (1–4). In T cells, Syk is mainly expressed ThegeneencodingSykhasalsobeenshowntobeaffected by guest on September 28, 2021 at the double-negative and double-positive (DP) developmental by chromosomal translocations. Chromosomal translocations are stages, but its expression is markedly reduced in later stages of thought to play a major role in the development and pathogenesis of T cell development (5, 6). Deregulated Syk expression or activity various malignancies. For example, the chromosomal translocation has been frequently linked to distinct hematological and non- t (9, 12)(q22;p12) was identified in a patient with myelodysplastic hematological malignancies and seems to play an important role syndrome and results in the expression of the TEL-Syk fusion in the development and maintenance of B cell lineage neoplasms. protein, leading to constitutive activation of Syk and the ability to For instance, inhibition of Syk induces apoptosis of chronic lym- transform various cell lines and induce leukemia in mice (10–12). Recently, an additional chromosomal translocation involving the Syk gene, the t (5, 9)(q33;q22), was found in ∼17% of unspecified † *Institute of Immunology, University Clinics Ulm, 89081 Ulm, Germany; Department PTCLs, which represent a heterogeneous and aggressive group of of Molecular Immunology, Faculty of Biology, Albert-Ludwigs University of Freiburg and Max Planck Institute of Immunobiology and Epigenetics, 79108 non-Hodgkin lymphomas (13). This translocation fuses Syk to the Freiburg, Germany; ‡Institut fu¨r Klinische Chemie und Pathobiochemie, Klini- IL-2–inducible kinase (ITK) and results in an ITK-Syk fusion kum rechts der Isar, Technische Universita¨tMu¨nchen, 81675 Munich, Germany; xDepartment of Hematology/Oncology, University Medical Center Freiburg, transcript. ITK is a member of the Tec kinase family, predomi- 79106 Freiburg, Germany; and {German Cancer Consortium, German Cancer nantly expressed in T cells and involved in normal T cell devel- Research Center, 69120 Heidelberg, Germany opment and activation. Mice deficient for ITK show a partial block Received for publication February 11, 2013. Accepted for publication November 25, in T cell development and impaired signaling downstream of the 2013. TCR (14). Upon TCR activation, ITK is recruited to the mem- This work was supported by the Deutsche Krebshilfe (Project 108935) and the Deutsche Forschungsgemeinschaft (SFB746). brane in proximity of the TCR, where it is phosphorylated and Address correspondence and reprint requests to Prof. Hassan Jumaa, Institute of interacts with various substrates including linker for activation of Immunology, University Clinics Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany. T cells, SLP-76, Grb2, and phospholipase Cg1 (PLCg1) (15). ITK E-mail address: [email protected] localization to the plasma membrane is mediated by the pleckstrin The online version of this article contains supplemental material. homology (PH) domain of ITK and is dependent on PI3K activity Abbreviations used in this article: Bcl-6, B cell lymphoma-6; Blimp-1, B-lympho- that converts phosphatidylinositol-(4, 5)-bisphosphate to phos- cyte–induced maturation protein-1; CBA, cytometric bead array; DP, double-positive; hSyk, human spleen tyrosine kinase; IRF-4, IFN regulatory factor 4; ITK, IL-2– phatidylinositol-(3,4,5)-trisphosphate, the ligand for the PH do- inducible kinase; ITK-Syk, IL-2-inducible kinase–spleen tyrosine kinase; PH, pleck- main. Once activated, ITK phosphorylates PLCg1, which induces strin homology; PLCg1, phospholipase Cg1; PTCL, peripheral T cell lymphoma; SP, calcium mobilization and the activation of downstream pathways single-positive; Syk, spleen tyrosine kinase; wt, wild-type. regulating the activation and effector function of T cells (15). The Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 ITK-Syk fusion transcript contains the PH domain, the Tec ho- www.jimmunol.org/cgi/doi/10.4049/jimmunol.1300420 The Journal of Immunology 1025 mology domain of ITK, and the kinase domain of Syk. It was (Thr202/Tyr204; Cell Signaling Technology), anti–p-PKB (Ser473; Cell Sig- naling Technology), anti–p-ZAP70 (Tyr493; Cell Signaling Technology), demonstrated that this protein exhibits kinase activity and is 783 able to phosphorylate various important signaling proteins such anti–p-PLCg1(Tyr ; Cell Signaling Technology), and anti–Blimp-1 (C-21/ N-20; Santa Cruz Biotechnology). An APC labeling kit (AbD Serotec) or as PLCg1, Akt, and Erk1/2 (16, 17). secondary Ab (anti-rabbit DyLight-649; AbD Serotec) was used in case of To study the role of the ITK-Syk oncogene in disease development, unlabeled primary Abs. If not stated otherwise, Abs were obtained from BD we generated a mouse model for conditional ITK-Syk expression. Biosciences and eBioscience. Intracellular staining was performed using We found that T cell–specific ITK-Syk expression leads to a severe FIX&PERM Cell PermeabilizationKit(AnDerGrubBioResearch, Kaumberg, Austria). FACS analysis was performed with FACSCalibur or disease development with an early onset and aggressive polyclonal LSR II (BD Biosciences). Data were analyzed using FlowJo software lymphoproliferation by 7–9 wk of age, which is strikingly different (Tree Star). from available data showing that T cell–specific ITK-Syk expression Western blot analysis results in clonal
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