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* Department of Internal Medicine I, Division of Hematology and Hemostaseology,
Clinical Institute for Medical and Chemical Laboratory Diagnostics, and
Institute of Pharmacology, Medical University of Vienna, Austria;
Ludwig Boltzmann Institute for Clinical and Experimental Oncology and
¶ Skin Diseases Research Center, Department of Dermatology and Pathology, Columbia University, New York, NY 10027;
|| Research Center for Molecular Medicine of the Austrian Academy of Sciences and
# Ludwig Boltzmann Institute for Cancer Research, Vienna, Austria; and
** Institut National de la Santé et de la Recherche Médicale U563, Centre de Physiopathologie Toulouse Purpan, Purpan Hospital, Toulouse, France
Oncogenic tyrosine kinases (TK) usually convert growth factor-dependent cells to factor independence with autonomous proliferation. However, TK-driven neoplasms often are indolent and characterized by cell differentiation rather than proliferation. A prototype of an indolent TK-driven neoplasm is indolent systemic mastocytosis. We found that the D816V-mutated 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, IL-4 receptor, histamine, CD63, and ICAM-1 in IL-3-dependent BaF3 cells. By contrast, wild-type KIT did not induce cluster formation or mast cell differentiation Ags. Additionally, KIT D816V, but not wild-type KIT, induced STAT5 activation in BaF3 cells. However, despite these intriguing effects, KIT D816V did not convert BaF3 cells to factor-independent proliferation. Correspondingly, BaF3 cells with conditional expression 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 sufficient to cause indolent systemic mastocytosis, whereas additional defects may be required to induce aggressive mast cell disorders.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the Fonds zur Förderung der Wissenschaftlichen Forschung in Österreich (FWF) Grants P17205-B14, SFB no. F28, and SFB no. F18–20.
2 Address correspondence and reprint requests to Dr. Peter Valent, Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. E-mail address: peter.valent{at}meduniwien.ac.at
3 Abbreviations used in this paper: SM, systemic mastocytosis; MC, mast cell; ISM, indolent systemic mastocytosis; ASM, aggressive mastocytosis; MCL, mast cell leukemia; TK, tyrosine kinase; SCF, stem cell factor; wt, wild type; dn, dominant negative; tTR-KRAB, tetracycline repressor fused to the Kruppel-associated box repression domain of human Kox-1; pTyr, phosphotyrosine; IP, immunoprecipitation; HDC, histidine decarboxylase; MMCP5, mouse mast cell protease 5; MITF, microphthalmia transcription factor; LAMP-3, lysosome-associated protein 3; MML, myelomastocytic leukemia; IB, immunoblot; RFLP, restriction fragment length polymorphism; qPCR, quantitative PCR.
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