Symptomatic treatment of myelofibrosis by TGF-β1 signaling inhibition
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Myelofibrosis (MF) is a common complication of the Philadelphia-Chromosome negative (Ph-) myeloproliferative neoplasms (MPN) that responds poorly to current treatment regimens with Jak2 inhibitors. TGF-β1 is elevated in PMF patient plasma, progenitors and megakaryocytes (MK) and is known to be a crucial promoter of fibrosis through stimulation of fibroblasts and their progenitors, mesenchymal stroma cells (MSC). We tested the efficacy of an orally available inhibitor of the TGF-β receptor ALK5, Galunisertib, in counteracting fibrosis in two MF mouse models of common MPN oncogenes Jak2 and MPN. Transgenic Vav1-Jak2v617F mice show a Polycythemia Vera-like phenotype at 6 weeks old, progressing to fibrosis of bone marrow (BM) and spleen around 25-30 weeks. Thirty week old mice were treated with Galunisertib for 4 weeks and showed a significant decrease in fibrosis and spleen weight compared to control mice. Mice transplanted with BM cells transduced with MPLW515L rapidly develop MF, myeloproliferation and splenomegaly. Flow cytometry showed an expansion of immature and mature megakaryocytes with overexpression of TGF-β1 in MPLW515L cells. Treatment from day 12 to day 26 after transplantation significantly reduced fibrosis as measured by reticulin staining and hydroxyproline quantification. In vitro, ALK5 inhibition counteracted the pro-fibrotic effects of TGF-β1 on both murine and human MSC by antagonizing its stimulatory effects on collagen I and III production. This anti- fibrotic effect was replicated with another ALK5 inhibitor, vactosertib. Analysis of MSCs from Galunisertib-treated MPLW515L mice also showed reduced collagen I and III production compared to vehicle controls. In both MPN mouse models and in vitro assays of MPN patient samples, TGF-β1 signaling inhibition did not lead to clonal expansion, as had been reported for acute myeloid leukemia (AML) patient samples. In conclusion, we offer evidence that aberrant megakaryopoiesis drives TGF-β1 overproduction in MPN by increasing megakaryocyte numbers and overexpressing TGF-β1 in mutant MKs. ALK5 inhibition counteracts TGF-β1 induced fibrosis in two MPN mouse-models and is a promising candidate for antifibrotic treatment in MPNs without deleterious hematopoietic side effects.
Source: Dissertations Abstracts International, Volume: 80-06, Section: B.;Publisher info.: Dissertation/Thesis.;Advisors: Verma, Amit K.