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