Efficacy of BTI615 on malignant cells expansion and bone marrow fibrosis in a myelofibrosis mice model.

Abstract

6572 Background: Due to the limitation of Janus kinase inhibitors and allogeneic transplant, critical unmet needs are remained in myelofibrosis (MF) patients, particularly for those with cytopenias, non-response or intolerance issues. Novel therapeutic avenues could arise from promoting bone marrow regeneration, which is dysregulated by pro-tumorigenic, fibrotic niche networked by vicious cycle of transforming growth factor β (TGF-β) signaling. Here we verified that BTI615, a synthetic active TGF-β modulating peptide, rescued malignant cells expansion and bone marrow fibrosis to restore hematopoiesis in a romiplostim-induced MF model. Methods: Mice (5-6 weeks old C57BL/6J, male) were treated with romiplostim (s.c., 90 μg/kg, Q3D), and simultaneously dosed with BTI615 (i.v., 30 or 120 mg/kg, TIW) for 4 weeks. The bloods, femurs, and spleens were collected for cell counting, Hematoxylin and Eosin staining, Gordon & Sweet's silver staining, immunofluorescence imaging and cytokines quantification. Results: In blood, BTI615 restored the declined peripheral red blood cells and hemoglobin, and suppressed inflammatory increase of white blood cells (incl. monocytes and granulocytes). Histological examination of bone marrow and spleen revealed that BTI615 remarkably suppressed megakaryocytes hyperplasia and atypia. Moreover, there was a significant reduction in the deposition of reticular fibers, fibronectin and collagen IV over the femurs by BTI615. Notably, in BTI615 treated bone marrow, the specialized niches erythroblastic islands and total Ter-119 positive cells markedly increased, accompanied by declining trends of splenomegaly. Aligned with those symptom relieves, BTI615 decreased the amount of active TGF-β 1 and the intensity of phospho-Smad2, as well as the expression of interleukin (IL)-1α and monocyte chemoattractant protein (MCP)-1 in bone marrow. Conclusions: Given its effective suppression on hyperplasia of atypical megakaryocytes, inflammation, marrow fibrosis and the ultimate recovery of hematopoietic function via modulating TGF-β signaling, BTI615 has a great potential to be the next generation therapeutic approach for MF.