Myeloproliferative neoplasms (MPN) are accompanied by inflammation that arises in part through stimulation of cytokine production by the malignant clone, but which is also reinforced by cytokines secreted from the bone marrow microenvironment. In MPN Mesenchymal stromal cells (MSCs) of the microenvironment and their progeny can transform into cell types that support fibrotic processes. This malignant environment can further fuel altered signaling in the malignant clone besides therapy. Which factors are specifically secreted by the bone marrow niche, the cell types secreting these factors, and how this could be targeted to prevent persisting signaling in the malignant clone, is not fully understood. In this subproject, we are
- dissecting the expression and secretion patterns of chronic myeloid leukemia (CML) versus polycythemia vera (PV) MSC-derived progeny,
- evaluating the impact of microenvironmental factors on CML and PV stem cell survival in vitro using receptor fusion proteins (RFPs) to target cytokines, and
- investigating the effect of cytokine inhibition on MPN development using RFP as well as a gene delivery approach with a special focus on the JAK1-STAT3 activating cytokines interleukin-6 (IL-6) and oncostatin M (OSM).
This project is providing novel insights into the mechanisms driving therapy-persistence within the malignant clone, induced by the tumor niche, and fibrosis.