Cell Reports (Jan 2024)
Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms
- Jessica E. Pritchard,
- Juliette E. Pearce,
- Inge A.M. Snoeren,
- Stijn N.R. Fuchs,
- Katrin Götz,
- Fabian Peisker,
- Silke Wagner,
- Adam Benabid,
- Niklas Lutterbach,
- Vanessa Klöker,
- James S. Nagai,
- Monica T. Hannani,
- Anna K. Galyga,
- Ellen Sistemich,
- Bella Banjanin,
- Niclas Flosdorf,
- Eric Bindels,
- Kathrin Olschok,
- Katharina Biaesch,
- Nicolas Chatain,
- Neha Bhagwat,
- Andrew Dunbar,
- Rita Sarkis,
- Olaia Naveiras,
- Marie-Luise Berres,
- Steffen Koschmieder,
- Ross L. Levine,
- Ivan G. Costa,
- Hélène F.E. Gleitz,
- Rafael Kramann,
- Rebekka K. Schneider
Affiliations
- Jessica E. Pritchard
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany; Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands; Oncode Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
- Juliette E. Pearce
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Inge A.M. Snoeren
- Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands; Oncode Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
- Stijn N.R. Fuchs
- Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands; Oncode Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
- Katrin Götz
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Fabian Peisker
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Hospital, Aachen, Germany
- Silke Wagner
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Adam Benabid
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Niklas Lutterbach
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Vanessa Klöker
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
- James S. Nagai
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
- Monica T. Hannani
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Hospital, Aachen, Germany; Institute for Computational Biomedicine, Heidelberg University Hospital, Heidelberg, Germany
- Anna K. Galyga
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Ellen Sistemich
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Bella Banjanin
- Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands; Oncode Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
- Niclas Flosdorf
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany
- Eric Bindels
- Department of Hematology, Erasmus Medical Center, Rotterdam, the Netherlands
- Kathrin Olschok
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
- Katharina Biaesch
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
- Nicolas Chatain
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
- Neha Bhagwat
- Prelude Therapeutics, Wilmington, DE, USA
- Andrew Dunbar
- Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Rita Sarkis
- Laboratory of Regenerative Hematopoiesis, Department of Biomedical Sciences (DSB), Université de Lausanne (UNIL), Lausanne, Switzerland
- Olaia Naveiras
- Laboratory of Regenerative Hematopoiesis, Department of Biomedical Sciences (DSB), Université de Lausanne (UNIL), Lausanne, Switzerland
- Marie-Luise Berres
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany; Medical Department III, RWTH University Hospital Aachen, Aachen, Germany
- Steffen Koschmieder
- Department of Hematology, Oncology, Hemostaseology, and Stem Cell Transplantation, RWTH Aachen University Hospital, Aachen, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Aachen, Germany
- Ross L. Levine
- Human Oncology and Pathogenesis Program, Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Ivan G. Costa
- Institute for Computational Genomics, RWTH Aachen University Hospital, Aachen, Germany
- Hélène F.E. Gleitz
- Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands; Oncode Institute, Erasmus University Medical Center, Rotterdam, the Netherlands
- Rafael Kramann
- Institute of Experimental Medicine and Systems Biology, RWTH Aachen University Hospital, Aachen, Germany; Department of Internal Medicine, Nephrology and Transplantation, Erasmus University Medical Center, Rotterdam, the Netherlands; Department of Nephrology and Clinical Immunology, RWTH Aachen University Hospital, Aachen, Germany
- Rebekka K. Schneider
- Institute for Cell and Tumor Biology, RWTH Aachen University Hospital, Aachen, Germany; Department of Developmental Biology, Erasmus University Medical Center, Rotterdam, the Netherlands; Oncode Institute, Erasmus University Medical Center, Rotterdam, the Netherlands; Corresponding author
- Journal volume & issue
-
Vol. 43,
no. 1
p. 113608
Abstract
Summary: The role of hematopoietic Hedgehog signaling in myeloproliferative neoplasms (MPNs) remains incompletely understood despite data suggesting that Hedgehog (Hh) pathway inhibitors have therapeutic activity in patients. We aim to systematically interrogate the role of canonical vs. non-canonical Hh signaling in MPNs. We show that Gli1 protein levels in patient peripheral blood mononuclear cells (PBMCs) mark fibrotic progression and that, in murine MPN models, absence of hematopoietic Gli1, but not Gli2 or Smo, significantly reduces MPN phenotype and fibrosis, indicating that GLI1 in the MPN clone can be activated in a non-canonical fashion. Additionally, we establish that hematopoietic Gli1 has a significant effect on stromal cells, mediated through a druggable MIF-CD74 axis. These data highlight the complex interplay between alterations in the MPN clone and activation of stromal cells and indicate that Gli1 represents a promising therapeutic target in MPNs, particularly that Hh signaling is dispensable for normal hematopoiesis.
