Inhibiting the alarmin-driven hematopoiesis-stromal cell crosstalk in primary myelofibrosis ameliorates bone marrow fibrosis.

Inflammation from the hematopoietic compartment is a critical driver of fibrosis and cytopenias in myeloproliferative neoplasms (MPNs). We previously demonstrated that tasquinimod ameliorates the MPN phenotype, reducing splenomegaly and normalizing fibrosis in a JAK2V617F-driven preclinical model. Using bulk RNA sequencing, we now show that tasquinimod primarily targets the malignant JAK2V617F hematopoietic clone, particularly affecting megakaryocytes and monocytes. Tasquinimod downregulates pro-proliferative pathways, MYC targets, and mTORC signaling, while increasing apoptosis in particularly in JAK2V617F mutant cells. Our data reveal that tasquinimod reverses TGFβ-driven fibrotic reprogramming of megakaryocytes and monocytes. This reversal is crucial for mitigating the pro-fibrotic interactions and signaling in the BM, thereby decreasing the activation of stromal cells. Coculture experiments confirm that direct interaction between JAK2V617F hematopoietic cells and mesenchymal stromal cells upregulates S100A8 in stromal cells, independent of TGFβ alone. In line, genetic ablation of S100A9 in the hematopoietic but not stromal compartment significantly improves the MPN phenotype and normalizes BM fibrosis. Our data highlight the hematopoietic origin of the inflammatory signals driving fibrosis. These insights pave the way for potential therapeutic strategies targeting inflammatory signaling pathways in MPN to mitigate fibrosis and improve patient outcomes.