TGFβ1 protein trap AVID200 beneficially affects hematopoiesis and bone marrow fibrosis in myelofibrosis

Myelofibrosis (MF) is a progressive chronic myeloproliferative neoplasm characterized by hyperactivation of JAK/STAT signaling and dysregulation of the transcription factor GATA1 in megakaryocytes (MKs). TGFβ plays a pivotal role in the pathobiology of MF by promoting bone marrow fibrosis and collagen deposition and by enhancing the dormancy of normal hematopoietic stem cells (HSCs). In this study, we show that MF MKs elaborated significantly greater levels of TGFβ1 than TGFβ2 and TGFβ3 to a varying degree, and evaluated the ability of AVID200 a potent TGFβ1/3 protein trap, to block the excessive TGFβ signaling. Treatment of human mesenchymal stromal cells (MSCs) with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGFβ1 to induce collagen expression. Moreover, treatment of MF mononuclear cells (MNCs) with AVID200 led to increased numbers of progenitor cells (PC) with wild type JAK2 rather than mutated JAK2V617F. This effect of AVID200 on MF PC was attributed to its ability to block TGFβ1-induced p57Kip2 expression and SMAD2 activation thereby allowing normal rather than MF PCs to preferentially proliferate, and form hematopoietic colonies. To assess the in vivo effects of AVID200, Gata1low mice, a murine model of MF, were treated with AVID200 resulting in the reduction in bone marrow (BM) fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short and long term HSCs.Collectively, these data provide the rationale for TGFβ1 blockade with AVID200 as a therapeutic strategy for MF patients.