Project Details
Projekt
Molecular targeting of STAT3-activating cytokines in the MPN pre-fibrotic niche
Subject Area
Hematology, Oncology
Term
since 2019
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 417911533
Myeloproliferative neoplasms (MPN) are accompanied by inflammation that arises from cytokines secreted by the malignant clone and its progeny which is reinforced by reactive cytokine production from the bone marrow microenvironment. This inflammatory phenotype, a hallmark of the disease, promotes fibrotic transformation of mesenchymal stroma cells resulting in bone marrow fibrosis but also supports survival of leukemic stem cells (LSCs). The goal of this project is to characterize and block the activities of relevant cytokines such as insulin-like growth factor-1 (IGF-1) and one of its binding proteins (IGFBP2) as well as interleukin-6 (IL-6) and oncostatin M (OSM). In the first funding period, the IGF-1/IGFBP2 axis has been identified as a potential mediator of fibrosis and stem cell persistence in CML. Furthermore, using a receptor fusion protein (RFP) as a highly specific and potent inhibitor, OSM has been shown to be a relevant factor in the MPN pre-fibrotic niche in mice. An RFP is encoded by a single gene and therefore perfectly suited for application via gene delivery. We have shown that IL-6, another relevant factor in MPN, can be inhibited by lentiviral gene delivery of an IL-6-RFP in myeloid cells. The present proposal aims to investigate the impact of the observed increased IGFBP2 levels on the hematopoietic system and on the LSC-propagating niche in CML and to define the cellular source of IGFBP2. The therapeutic potential of IGFBP2/IGF-1 receptor inhibition will be evaluated in CML mice and primary patient samples. Lentiviral gene delivery of OSM-RFP will be used to analyze the effect of OSM inhibition on the fibrotic phenotype in human cellular fibrosis models based on patient-derived induced pluripotent stem cells (iPSCs) to define OSM as a relevant factor in human disease. Finally, delivery of RFP mRNA through lipid nanoparticles (LNPs) will be established as a therapeutic option in preclinical MPN models. The project will provide novel insights into the mechanisms of stem cell persistence and fibrotic transformation in MPN and will develop novel options for therapeutic interventions.
DFG Programme
Clinical Research Units
