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

Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis. Cell Stem Cell. 2020 Dec 09;: Authors: Leimkühler NB, Gleitz HFE, Ronghui L, Snoeren IAM, Fuchs SNR, Nagai JS, Banjanin B, Lam KH, Vogl T, Kuppe C, Stalmann USA, Büsche G, Kreipe H, Gütgemann I, Krebs P, Banz Y, Boor P, Tai EW, Brümmendorf TH, Koschmieder S, Crysandt M, Bindels E, Kramann R, Costa IG, Schneider RK Abstract 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 attractiv...
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research