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G Greiner, N Witzeneder, A Berger, K Schmetterer, G Eisenwort, AI Schiefer, S Roos, T Popow-Kraupp, L Müllauer, J Zuber, V Sexl, L Kenner, WR Sperr, P Valent, M Mayerhofer and G Hoermann
Abstract
Systemic mastocytosis (SM) is characterized by abnormal accumulation of neoplastic mast cells harboring the activating KIT mutation D816V in the bone marrow and other internal organs. Similar to other myeloproliferative neoplasms, increased production of pro-fibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, only little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the pro-angiogenic cytokine CCL-2 in neoplastic mast cells. Correspondingly, the KIT-targeting drug midostaurin and RNAi-mediated knockdown of KIT reduced expression of CCL-2. We also found that NFκB contributes to KIT-dependent upregulation of CCL-2 in mast cells. In addition, CCL-2 secreted by KIT D816V+ mast cells was found to promote the migration of human endothelial cells in vitro Furthermore, knockdown of CCL-2 in neoplastic mast cells resulted in reduced microvessel density and reduced tumor growth in NSG mice in vivo, compared to CCL-2-expressing cells. Finally, we measured CCL-2 serum concentrations in patients with SM and found that CCL-2 levels were significantly elevated in mastocytosis patients compared to controls. Furthermore, CCL-2 serum levels were higher in patients with advanced SM and were found to correlate with poor survival. In summary, we have identified CCL-2 as a novel, KIT D816V-dependent, key regulator of vascular cell migration and angiogenesis in SM. CCL-2 expression correlates with disease severity and prognosis. Whether CCL-2 may serve as a therapeutic target in advanced SM remains to be determined in forthcoming studies.
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Concepts
Angiogenesis, Endothelium, Organ, Mastocytosis, Immune system, Heart, Mast cell, Cancer
MeSH headings
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