Summary

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.

Overall design

We used scRNA 3' RNA sequencing product from 10x Genomics to profile human non-fibrotic bone marrow as well as bone marrow with diagnosed myelofibrosis

Contributors

Nils B Leimkühler 1, Hélène F E Gleitz 1, Li Ronghui 2, Inge A M Snoeren 1, Stijn N R Fuchs 1, James S Nagai 2, Bella Banjanin 1, King H Lam 3, Thomas Vogl 4, Christoph Kuppe 5, Ursula S A Stalmann 1, Guntram Büsche 6, Hans Kreipe 6, Ines Gütgemann 7, Philippe Krebs 8, Yara Banz 8, Peter Boor 9, Evelyn Wing-Yin Tai 9, Tim H Brümmendorf 10, Steffen Koschmieder 10, Martina Crysandt 10, Eric Bindels 1, Rafael Kramann 11, Ivan G Costa 2, Rebekka K Schneider 12

Contact

reschneider@ukaachen.de.(Rebekka K Schneider)