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

doi:10.1016/j.celrep.2023.113608

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 ChatainNeha 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^*

^*Corresponding author for this work

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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.

Original language	English
Article number	113608
Journal	Cell Reports
Volume	43
Issue number	1
DOIs	https://doi.org/10.1016/j.celrep.2023.113608
Publication status	Published - 23 Jan 2024

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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., ... Schneider, R. K. (2024). Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms. Cell Reports, 43(1), Article 113608. https://doi.org/10.1016/j.celrep.2023.113608

@article{a32391a7118e4797a2ba0b829eba4a6d,

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.",

author = "Pritchard, {Jessica E.} and Pearce, {Juliette E.} and Snoeren, {Inge A.M.} and Fuchs, {Stijn N.R.} and Katrin G{\"o}tz and Fabian Peisker and Silke Wagner and Adam Benabid and Niklas Lutterbach and Vanessa Kl{\"o}ker and Nagai, {James S.} and Hannani, {Monica T.} and Galyga, {Anna K.} and Ellen Sistemich and Bella Banjanin and Niclas Flosdorf and Eric Bindels and Kathrin Olschok and Katharina Biaesch and Nicolas Chatain and Neha Bhagwat and Andrew Dunbar and Rita Sarkis and Olaia Naveiras and Berres, {Marie Luise} and Steffen Koschmieder and Levine, {Ross L.} and Costa, {Ivan G.} and Gleitz, {H{\'e}l{\`e}ne F.E.} and Rafael Kramann and Schneider, {Rebekka K.}",

note = "Publisher Copyright: {\textcopyright} 2023 The Authors",

year = "2024",

month = jan,

day = "23",

doi = "10.1016/j.celrep.2023.113608",

language = "English",

volume = "43",

journal = "Cell Reports",

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Pritchard, JE, Pearce, JE, Snoeren, IAM, Fuchs, SNR, Götz, K, Peisker, F, Wagner, S, Benabid, A, Lutterbach, N, Klöker, V, Nagai, JS, Hannani, MT, Galyga, AK, Sistemich, E, Banjanin, B, Flosdorf, N, Bindels, E, Olschok, K, Biaesch, K, Chatain, N, Bhagwat, N, Dunbar, A, Sarkis, R, Naveiras, O, Berres, ML, Koschmieder, S, Levine, RL, Costa, IG, Gleitz, HFE , Kramann, R & Schneider, RK 2024, 'Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms', Cell Reports, vol. 43, no. 1, 113608. https://doi.org/10.1016/j.celrep.2023.113608

TY - JOUR

T1 - Non-canonical Hedgehog signaling mediates profibrotic hematopoiesis-stroma crosstalk in myeloproliferative neoplasms

AU - Pritchard, Jessica E.

AU - Pearce, Juliette E.

AU - Snoeren, Inge A.M.

AU - Fuchs, Stijn N.R.

AU - Götz, Katrin

AU - Peisker, Fabian

AU - Wagner, Silke

AU - Benabid, Adam

AU - Lutterbach, Niklas

AU - Klöker, Vanessa

AU - Nagai, James S.

AU - Hannani, Monica T.

AU - Galyga, Anna K.

AU - Sistemich, Ellen

AU - Banjanin, Bella

AU - Flosdorf, Niclas

AU - Bindels, Eric

AU - Olschok, Kathrin

AU - Biaesch, Katharina

AU - Chatain, Nicolas

AU - Bhagwat, Neha

AU - Dunbar, Andrew

AU - Sarkis, Rita

AU - Naveiras, Olaia

AU - Berres, Marie Luise

AU - Koschmieder, Steffen

AU - Levine, Ross L.

AU - Costa, Ivan G.

AU - Gleitz, Hélène F.E.

AU - Kramann, Rafael

AU - Schneider, Rebekka K.

PY - 2024/1/23

Y1 - 2024/1/23

N2 - 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.

AB - 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.

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U2 - 10.1016/j.celrep.2023.113608

DO - 10.1016/j.celrep.2023.113608

M3 - Article

C2 - 38117649

AN - SCOPUS:85180344666

SN - 2211-1247

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 1

M1 - 113608

ER -

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

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