Interferon alpha (IFNa) induces clinical and molecular remissions in patients with polycythemia (PV), essential thrombocythemia (ET) or early primary myelofibrosis (prePMF), but responses vary considerably. Currently, the factors which determine response in MF patients are unknown. This subproject aims to elucidate the mechanisms of IFNa and other regimens on BM fibrosis and distinguish these from effects on the hematopoietic clone. Specifically, we are
- assessing the biological effects of IFNa on hematopoietic and non-hematopoietic cells from murine MPN models by performing RNAseq analysis and loss- and gain-of-function assays and dissecting IFNa-induced STAT3 activation in stromal vs. hematopoietic cells, and
- analyzing the effects of IFNa vs. other MPN-specific treatments on human BM fibroblasts, myofibroblasts and megakaryocytes utilizing BM trephine biopsies of MPN patients (PV, ET, prePMF, overtPMF) treated with IFNa, hydroxyurea, or anagrelide.
Together, these experiments will lead to a better understanding of the effects of IFNa on BM stromal cells and which obstacles need to be overcome in order to render patients with overt myelofibrosis responsive to IFNa.