Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis

• DOI: 10.1016/j.stem.2020.11.004
• Publication Date: 2020-12-09T22:53:14Z
• Authors: Nils B. Leimkühler; Hélène F.E. Gleitz; Li Ronghui; Inge A.M. Snoeren; Stijn N.R. Fuchs; James S. Nagai; Bella Banjanin; King H. Lam; Thomas Vogl; Christoph Kuppe; Ursula S.A. Stalmann; Guntram Büsche; Hans Kreipe; Ines Gütgemann; Philippe Krebs; Yara Banz; Peter Boor; Evelyn Wing-Yin Tai; Tim H. Brümmendorf; Steffen Koschmieder; Martina Crysandt; Eric Bindels; Rafael Kramann; Ivan G. Costa; Rebekka K. Schneider
• Keywords: Druggability

Functional contributions of individual cellular components the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. We aimed generate a comprehensive map stroma MPNs/MFs on single-cell level murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed stage-dependent manner loss their progenitor status initiation differentiation pre-fibrotic acquisition inflammatory phenotype fibrotic stage. The expression alarmin complex S100A8/S100A9 MSC marked disease progression toward phase plasma. Tasquinimod, small-molecule inhibiting signaling, significantly ameliorated MPN fibrosis JAK2V617F-mutated models, highlighting that is an attractive therapeutic target MPNs.