Bone marrow fibrosis (BMF), in the myeloproliferative neoplasm (MPN) myelofibrosis (MF), is the result of a complex and yet not fully understood interaction between megakaryocytes, monocytes, fibroblasts, endothelial cells, cytokines and marrow stroma [1]. There are substantial data to support the clonal nature of MPNs from primitive progenitor hematopoietic cells which then secrete factors that activate polyclonal fibroblasts in the bone marrow [2]. BMF is not an irreversible process, and morphologic evidence of reversal can be achieved after hematopoietic stem cell transplant and occasionally drug therapy [3–5]. Transforming growth factor-β (TGF-β) is a pleiotropic cytokine implicated in the promotion of angiogenesis, tumor growth, collagen fibrosis, metastatic spread and down-regulation of antitumor immunity, and paradoxically, tumor-suppressive effects [6]. TGF-β likely plays a dual role in promoting myelofibrosis and myeloproliferation, both of which are the morphologic hallmarks of MF [2]. Degree of BMF can be correlated with a variety of clinical features such as anemia, thrombocytopenia, leukopenia, splenomegaly and peripheral blood blasts, and can be predictive of survival in patients with MF [7, 8].

Preclinical studies support a pathobiological role of TGF-β in MF [9–11]. The development of BMF in GATA-1 low and TPO high murine models of MF is associated with high levels of TGF-β expression in extracellular fluids and spaces within the bone marrow and spleen [10]. A working hypothesis linking abnormal megakaryocyte/neutrophil interaction with enhanced TGF-β expression in MF has been developed based on these observations [11]. Para-apoptosis leading to the release of TGF-β from megakaryocyte alpha-granules may be the result of impaired neutrophil emperipolesis due to abnormal P-selectin localization on the demarcation membrane of MF megakaryocytes [10]. Additionally, TGF-β mRNA levels are significantly elevated in megakaryocytes of patients with MF and correlate with the degree of BMF [9]. We hypothesized that inhibiting the TGF-β signaling pathway in MF would decrease the fibrogenic stimuli leading to BMF and concomitantly interrupt myeloproliferation.