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

Leimkühler, Nils B.; Gleitz, Hélène F.E.; Ronghui, Li; Snoeren, Inge A.M.; Fuchs, Stijn N.R.; Nagai, James S.; Banjanin, Bella; Lam, King H.; Vogl, Thomas; Kuppe, Christoph; Stalmann, Ursula S.A.; Büsche, Guntram; Kreipe, Hans; Gütgemann, Ines; Krebs, Philippe; Banz, Yara; Boor, Peter; Tai, Evelyn Wing-Ying; Brümmendorf, Tim H.; Koschmieder, Steffen; ... (2020). Heterogeneous bone-marrow stromal progenitors drive myelofibrosis via a druggable alarmin axis (In Press). Cell stem cell Elsevier 10.1016/j.stem.2020.11.004

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Service Sector > Institute of Pathology > Cytopathology
04 Faculty of Medicine > Service Sector > Institute of Pathology
04 Faculty of Medicine > Service Sector > Institute of Pathology > Immunopathology

UniBE Contributor:

Krebs, Philippe and Banz Wälti, Yara

Subjects:

500 Science > 570 Life sciences; biology
600 Technology > 610 Medicine & health

ISSN:

1934-5909

Publisher:

Elsevier

Language:

English

Submitter:

Philippe Krebs

Date Deposited:

24 Dec 2020 12:02

Last Modified:

25 Dec 2020 01:34

Publisher DOI:

10.1016/j.stem.2020.11.004

PubMed ID:

33301706

Uncontrolled Keywords:

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

BORIS DOI:

10.7892/boris.149432

URI:

https://boris.unibe.ch/id/eprint/149432

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