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

alarmins, biomarker, bone marrow fibrosis, DAMP, drug target, hematopoietic stem cells, mesenchymal stromal cells, microenvironment, myeloproliferative neoplasms, single cell RNA sequencing,
Cell Stem Cell
Department of Hematology

Leimkühler, N.B. (Nils B.), Gleitz, H.F.E, Ronghui, L. (Li), Snoeren, I.A.M. (Inge A.M.), Fuchs, S.N.R. (Stijn N.R.), Nagai, J.S. (James S.), … Schneider-Kramann, R.K.M. (2020). Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis. Cell Stem Cell. doi:10.1016/j.stem.2020.11.004