TY - JOUR AU - Araceli Tobío, AU - Geethani Bandara, AU - Denise A. Morris, AU - Do-Kyun Kim, AU - Michael P. O’Connell, AU - Hirsh D. Komarow, AU - Melody C. Carter, AU - Daniel Smrz, AU - Dean D. Metcalfe, AU - Ana Olivera, PY - 2020/01/01 Y2 - 2024/03/29 TI - Oncogenic D816V-KIT signaling in mast cells causes persistent IL-6 production JF - Haematologica JA - haematol VL - 105 IS - 1 SE - Articles DO - 10.3324/haematol.2018.212126 UR - https://haematologica.org/article/view/9482 SP - 124-135 AB - Persistent dysregulation of IL-6 production and signaling have been implicated in the pathology of various cancers. In systemic mastocytosis, increased serum levels of IL-6 associate with disease severity and progression, although the mechanisms involved are not well understood. Since systemic mastocytosis often associates with the presence in hematopoietic cells of a somatic gain-of-function variant in KIT, D816V-KIT, we examined its potential role in IL-6 upregulation. Bone marrow mononuclear cultures from patients with greater D816V allelic burden released increased amounts of IL-6 which correlated with the percentage of mast cells in the cultures. Intracellular IL-6 staining by flow cytometry and immunofluorescence was primarily associated with mast cells and suggested a higher percentage of IL-6 positive mast cells in patients with higher D816V allelic burden. Furthermore, mast cell lines expressing D816V-KIT, but not those expressing normal KIT or other KIT variants, produced constitutively high IL-6 amounts at the message and protein levels. We further demonstrate that aberrant KIT activity and signaling are critical for the induction of IL-6 and involve STAT5 and PI3K pathways but not STAT3 or STAT4. Activation of STAT5A and STAT5B downstream of D816V-KIT was mediated by JAK2 but also by MEK/ERK1/2, which not only promoted STAT5 phosphorylation but also its long-term transcription. Our study thus supports a role for mast cells and D816V-KIT activity in IL-6 dysregulation in mastocytosis and provides insights into the intracellular mechanisms. The findings contribute to a better understanding of the physiopathology of mastocytosis and suggest the importance of therapeutic targeting of these pathways. ER -