Abstract
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). TGF-β plays a pivotal role in the pathobiology of MF by promoting BM 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 TGF-β1 than TGF-β2 and TGF-β3 to a varying degree, and we evaluated the ability of AVID200, a potent TGF-β1/TGF-β3 protein trap, to block the excessive TGF-β signaling. Treatment of human mesenchymal stromal cells with AVID200 significantly reduced their proliferation, decreased phosphorylation of SMAD2, and interfered with the ability of TGF-β1 to induce collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PCs) with WT JAK2 rather than mutated JAK2V617F. This effect of AVID200 on MF PCs was attributed to its ability to block TGF-β1–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, Gata1lo mice, a murine model of MF, were treated with AVID200, resulting in the reduction in BM fibrosis and an increase in BM cellularity. AVID200 treatment also increased the frequency and numbers of murine progenitor cells as well as short-term and long-term HSCs. Collectively, these data provide the rationale for TGF-β1 blockade, with AVID200 as a therapeutic strategy for patients with MF.
Highlights
Myelofibrosis (MF) is a clonal hematopoietic stem cell (HSC) disorder for which there are limited therapeutic options
The levels of TGF-β2 and TGF-β3 were lower than TGF-β1 in both normal donors (NDs)-MK and MF-MK conditioned media (CM) (Figure 1B)
We measured the effects of rTGF-β1, rTGF-β2, and rTGF-β3 on the phosphorylation of SMAD2 in MF mononuclear cells (MNCs) after 4 days of culture (Supplemental Figure 3)
Summary
Myelofibrosis (MF) is a clonal hematopoietic stem cell (HSC) disorder for which there are limited therapeutic options. Patients with symptomatic disease have improvement in their quality of life with the administration of JAK1/2 inhibitors [1,2,3] These medications are frequently effective, they have a limited impact on prolonging survival, and eventually patients frequently become intolerant or refractory to their action [4]. The only curative approach for patients with MF remains allogeneic HSC transplantation [5]. These limitations have led to a search for alternative drugs that might affect other relevant MF pathological pathways. MF is characterized by BM megakaryocyte (MK) hyperplasia These MKs release excess proinflammatory cytokines and growth factors, altering the hematopoietic microenvironment in a manner that supports MF HSC/hematopoietic progenitor cell (HSC/HPC) predominance [6,7,8]. MKs are not the only source of TGF-β in MF because macrophages and monocytes as well as other accessory cell types elaborate increased levels of this cytokine [10]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
