Unique Effects of KIT D816V in BaF3 Cells

Unique Effects of KIT D816V in BaF3 Cells

12 Pages · 2008 · 752 KB · English

D816V induces indolent mast cell accumulations but usually does not induce a 2 Address correspondence and reprint requests to Dr. Peter Valent, Department of D816V.27 cells were cultured in control medium (gray graph).

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of May 15, 2019 This information is current as Differentiation Antigens Synthesis, and Early Mast Cell Induction of Cluster Formation, Histamine Unique Effects of KIT D816V in BaF3 Cells: Valent Schwarzinger, Veronika Sexl, Christian Sillaber and Peter Richard Moriggl, Jacques Zappulla, Roland S Liblau, Ilse Wolfgang R Sperr, Jack B Longley, Robert Kralovics, Martin Bilban, Harald Esterbauer, MariaTheresa Krauth, Stefan Florian, Gregor Hoermann, Karl J Aichberger, Matthias Mayerhofer, Karoline V Gleixner, Andrea Hoelbl, http://wwwjimmunolorg/content/180/8/5466 doi: 104049/jimmunol180854662008; 180:54665476; ; J Immunol  References http://wwwjimmunolorg/content/180/8/5466full#reflist1 , 25 of which you can access for free at: cites 51 articles This article         average *    4 weeks from acceptance to publication Fast Publication!  •     Every submission reviewed by practicing scientists No Triage!  •     from submission to initial decision Rapid Reviews! 30 days*  •     Submit online   ? The JI Why Subscription http://jimmunolorg/subscription is online at: The Journal of Immunology Information about subscribing to Permissions http://wwwaaiorg/About/Publications/JI/copyrighthtml Submit copyright permission requests at: Email Alerts http://jimmunolorg/alerts Receive free emailalerts when new articles cite this article Sign up a\ t: Print ISSN: 00221767 Online ISSN: 15506606 Immunologists All rights reserved Copyright © 2008 by The American Association of 1451 Rockville Pike, Suite 650, Rockville, MD 20852 The American Association of Immunologists, Inc, is published twice each month by The Journal of Immunology by guest on May 15, 2019 http://wwwjimmunolorg/ Downloaded from by guest on May 15, 2019 http://wwwjimmunolorg/ Downloaded from Unique Effects of KIT D816V in BaF3 Cells: Induction of Cluster Formation, Histamine Synthesis, and Early Mast Cell Differentiation Antigens 1 Matthias Mayerhofer,* †Karoline V Gleixner,* Andrea Hoelbl, ‡Stefan Florian,* Gregor Hoermann,* †Karl J Aichberger,* Martin Bilban, †§ Harald Esterbauer, † MariaTheresa Krauth,* Wolfgang R Sperr,* Jack B Longley, ¶Robert Kralovics,  Richard Moriggl, #Jacques Zappulla,** Roland S Liblau,** Ilse Schwarzinger, † Veronika Sexl, ‡Christian Sillaber,* and Peter Valent 2* Oncogenic tyrosine kinases (TK) usually convert growth factordependent cells to factor independence with autonomous prolif eration However, TKdriven neoplasms often are indolent and characterized by cell differentiation rather than proliferation A prototype of an indolent TKdriven neoplasm is indolent systemic mastocytosis We found that the D816Vmutated variant of KIT, a TK detectable in most patients with systemic mastocytosis, induces cluster formation and expression of several mast cell differentiation and adhesion Ags, including microphthalmia transcription factor, IL4 receptor, histamine, CD63, and ICAM1 in IL3dependent BaF3 cells By contrast, wildtype KIT did not induce cluster formation or mast cell differentiation Ags Addi tionally, KIT D816V, but not wildtype KIT, induced STAT5 activation in BaF3 cells However, despite these intriguing effects, KIT D816V did not convert BaF3 cells to factorindependent proliferation Correspondingly, BaF3 cells with conditional expres sion of KIT D816V did not form tumors in nude mice Together, the biologic effects of KIT D816V in BaF3 cells match strikingly with the clinical course of indolent systemic mastocytosis and with our recently established transgenic mouse model, in which KIT D816V induces indolent mast cell accumulations but usually does not induce a malignant mast cell disease Based on all these results, it is hypothesized that KIT D816V as a single hit may be sufcient to cause indolent systemic mastocytosis, whereas additional defects may be required to induce aggressive mast cell disorders The Journal of Immunology,2008, 180: 5466 –5476 S ystemic mastocytosis (SM) 3is a neoplastic disease of mast cells (MC) and their bone marrowderived progenitors (1, 2) Indolent and aggressive variants of the disease have been described In most adult patients, indolent systemic masto cytosis (ISM) is diagnosed These patients usually have typical (urticaria pigmentosalike) skin lesions and may suffer from me diatorrelated symptoms, but the disease does not behave as an overt malignancy (3, 4) Rather, despite accumulation of neoplastic MC, these patients have a normal or nearnormal life expectancy (4, 5) Clinically, most patients with ISM would even be over looked if they would not exhibit the striking cutaneous features of mastocytosis This is not the case in the rare aggressive variant of mastocytosis (ASM) or (the extremely rare) MC leukemia (MCL) In these patients, malignant MC proliferation is found and the sur vival

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