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

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

doi:10.1016/j.stem.2020.11.004

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

Cell Stem Cell. 2021 Apr 1;28(4):637-652.e8. doi: 10.1016/j.stem.2020.11.004. Epub 2020 Dec 9.

Authors

Nils B Leimkühler¹, Hélène F E Gleitz¹, Li Ronghui², Inge A M Snoeren¹, Stijn N R Fuchs¹, James S Nagai², Bella Banjanin¹, King H Lam³, Thomas Vogl⁴, Christoph Kuppe⁵, Ursula S A Stalmann¹, Guntram Büsche⁶, Hans Kreipe⁶, Ines Gütgemann⁷, Philippe Krebs⁸, Yara Banz⁸, Peter Boor⁹, Evelyn Wing-Yin Tai⁹, Tim H Brümmendorf¹⁰, Steffen Koschmieder¹⁰, Martina Crysandt¹⁰, Eric Bindels¹, Rafael Kramann¹¹, Ivan G Costa², Rebekka K Schneider¹²

Affiliations

¹ Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.
² Institute for Computational Genomics, Faculty of Medicine, RWTH Aachen University, Aachen 52074 Germany.
³ Department of Pathology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands.
⁴ Institute of Immunology, University of Münster, Münster 49148, Germany.
⁵ Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.
⁶ Institute of Pathology, Hannover Medical School, Hannover 30625, Germany.
⁷ Institute of Pathology, University of Bonn, Bonn 53127, Germany.
⁸ Institute of Pathology, University of Bern, Bern 3012, Switzerland.
⁹ Institute of Pathology, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.
¹⁰ Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany.
¹¹ Division of Nephrology and Clinical Immunology, Faculty of Medicine, RWTH Aachen University, Aachen 52074, Germany; Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen 52074, Germany.
¹² Department of Hematology, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands; Department of Cell Biology, Institute for Biomedical Engineering, Faculty of Medicine, RWTH Aachen University, Pauwelsstrasse 30, 52074 Aachen, Germany; Oncode Institute, Erasmus Medical Center, Rotterdam 3015GD, the Netherlands. Electronic address: reschneider@ukaachen.de.

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 attractive therapeutic target in MPNs.

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

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alarmins
Animals
Bone Marrow
Humans
Mesenchymal Stem Cells*
Mice
Myeloproliferative Disorders*
Primary Myelofibrosis*

Substances

Alarmins