Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms Journal Article
| Authors: | Pritchard, J. E.; Pearce, J. E.; Snoeren, I. A. M.; Fuchs, S. N. R.; Götz, K.; Peisker, F.; Wagner, S.; Benabid, A.; Lutterbach, N.; Klöker, V.; Nagai, J. S.; Hannani, M. T.; Galyga, A. K.; Sistemich, E.; Banjanin, B.; Flosdorf, N.; Bindels, E.; Olschok, K.; Biaesch, K.; Chatain, N.; Bhagwat, N.; Dunbar, A.; Sarkis, R.; Naveiras, O.; Berres, M. L.; Koschmieder, S.; Levine, R. L.; Costa, I. G.; Gleitz, H. F. E.; Kramann, R.; Schneider, R. K. |
| Article Title: | Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms |
| Abstract: | 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. © 2023 The Authors |
| Keywords: | hematopoietic stem cells; therapeutic target; myeloproliferative neoplasms; gli1; mesenchymal stromal cells; hedgehog signaling; bone marrow fibrosis; single-cell rna sequencing; cellular crosstalk; cp: stem cell research; mif |
| Journal Title: | Cell Reports |
| Volume: | 43 |
| Issue: | 1 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2024-01-23 |
| Start Page: | 113608 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2023.113608 |
| PROVIDER: | scopus |
| PUBMED: | 38117649 |
| PMCID: | PMC10828549 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in PubMed and PDF -- Source: Scopus |
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