Adipocytes - The cell of origin of fibrosis in MPN?

Myelofibrosis (MF) is a chronic myeloproliferative neoplasm characterized by splenomegaly and myelosuppression secondary to progressive marrow fibrosis. Although the discovery of the JAK2 and MPL mutations in >50% of MF patients was a major advance, JAK2 inhibitors have little impact on MF and consequent myelosuppression, and the pathogenesis of myelofibrosis remains poorly understood. Based on recent exciting preliminary results, we propose the innovative hypothesis that in MF, as in other forms of pathological fibrosis, in response to cytokines elicited from malignant myeloid precursors, adipogenic marrow mesenchymal progenitor cells switch cell fate resulting in preferential myofibroblast differentiation. Furthermore, we predict that pharmacological promotion of adipogenesis using novel agonists of PPAR-gamma will promote adipogenic differentiation while simultaneously suppress myofibroblast differentiation and ameliorate MF. Therefore, we propose two aims: i) use lineage tracing with genetically modified mice to document the accumulation of adipocyte-derived myofibroblasts in fibrotic bone marrow during experimental myelofibrosis; ii) show that novel synthetic PPAR-gamma agonists by preventing myofibroblast differentiation of adipocytic mesenchymal cells will ameliorate experimental MF in the mouse. This conceptually innovative proposal sets out a novel paradigm for the pathogenesis of MF and to test the therapeutic tractability of the paradigm in preclinical disease models. The project brings together an interdisciplinary research team with expertise in myeloid neoplasms, mesenchymal cell differentiation, fibrosis, and preclinical disease models. The findings from this pilot project will have significant implications for understanding MF and clear therapeutic relevance.