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Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

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 sig...

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Main Authors: Pritchard, Jessica E. (Author) , Pearce, Juliette E. (Author) , Snoeren, Inge A. M. (Author) , Fuchs, Stijn (Author) , Götz, Katrin (Author) , Peisker, Fabian (Author) , Wagner, Silke (Author) , Benabid, Adam (Author) , Lutterbach, Niklas (Author) , Klöker, Vanessa (Author) , Nagai, James S. (Author) , Hannani, Monica (Author) , Galyga, Anna K. (Author) , Sistemich, Ellen (Author) , Banjanin, Bella (Author) , Flosdorf, Niclas (Author) , Bindels, Eric (Author) , Olschok, Kathrin Claudia (Author) , Biaesch, Katharina (Author) , Chatain, Nicolas (Author) , Bhagwat, Neha (Author) , Douglas-Dunbar, Andrew (Author) , Sarkis, Rita (Author) , Naveiras, Olaia (Author) , Berres, Marie-Luise (Author) , Koschmieder, Steffen (Author) , Levine, Ross L. (Author) , Costa, Ivan G. (Author) , Gleitz, Hélène (Author) , Kramann, Rafael (Author) , Schneider-Kramann, Rebekka Katharina Marita (Author)
Format: Article (Journal)
Language:English
Published: 23 January 2024
In: Cell reports
Year: 2024, Volume: 43, Issue: 1, Pages: 1-27
ISSN:2211-1247
DOI:10.1016/j.celrep.2023.113608
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.celrep.2023.113608
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S2211124723016200
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Author Notes: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, and Rebekka K. Schneider
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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.
Item Description:Gesehen am 13.12.2024
Physical Description:Online Resource
ISSN:2211-1247
DOI:10.1016/j.celrep.2023.113608

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