Greiner, G; Witzeneder, N; Berger, A; Schmetterer, K; Eisenwort, G; Schiefer, AI; Roos, S; Popow-Kraupp, T; Müllauer, L; Zuber, J; Sexl, V; Kenner, L; Sperr, WR; Valent, P; Mayerhofer, M; Hoermann, G
CCL2 is a KIT D816V-dependent modulator of the bone marrow microenvironment in systemic mastocytosis.
Blood. 2017; 129(3):371-382
Autor/innen der Vetmeduni Vienna:
Institut für Pathologie, Abteilung für Labortierpathologie
Institut für Pharmakologie und Toxikologie
- 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. As found in other myeloproliferative neoplasms, increased production of profibrogenic and angiogenic cytokines and related alterations of the bone marrow microenvironment are commonly found in SM. However, little is known about mechanisms and effector molecules triggering fibrosis and angiogenesis in SM. Here we show that KIT D816V promotes expression of the proangiogenic cytokine CCL2 in neoplastic mast cells. Correspondingly, the KIT-targeting drug midostaurin and RNA interference-mediated knockdown of KIT reduced expression of CCL2. We also found that nuclear factor κB contributes to KIT-dependent upregulation of CCL2 in mast cells. In addition, CCL2 secreted by KIT D816V+ mast cells was found to promote the migration of human endothelial cells in vitro. Furthermore, knockdown of CCL2 in neoplastic mast cells resulted in reduced microvessel density and reduced tumor growth in vivo compared with CCL2-expressing cells. Finally, we measured CCL2 serum concentrations in patients with SM and found that CCL2 levels were significantly increased in mastocytosis patients compared with controls. CCL2 serum levels were higher in patients with advanced SM and were found to correlate with poor survival. In summary, we have identified CCL2 as a novel KIT D816V-dependent key regulator of vascular cell migration and angiogenesis in SM. CCL2 expression correlates with disease severity and prognosis. Whether CCL2 may serve as a therapeutic target in advanced SM remains to be determined in forthcoming studies.© 2017 by The American Society of Hematology.
Proto-Oncogene Proteins c-kitgenetics