Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN
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Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN. / Gleitz, Hélène F E; Dugourd, Aurélien J F; Leimkühler, Nils B; Snoeren, Inge A M; Fuchs, Stijn N R; Menzel, Sylvia; Ziegler, Susanne; Kröger, Nicolaus; Triviai, Ioanna; Büsche, Guntram; Kreipe, Hans; Banjanin, Bella; Pritchard, Jessica E; Hoogenboezem, Remco; Bindels, Eric M; Schumacher, Neele; Rose-John, Stefan; Elf, Shannon; Saez-Rodriguez, Julio; Kramann, Rafael; Schneider, Rebekka K.
In: BLOOD, Vol. 136, No. 18, 29.10.2020, p. 2051-2064.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN
AU - Gleitz, Hélène F E
AU - Dugourd, Aurélien J F
AU - Leimkühler, Nils B
AU - Snoeren, Inge A M
AU - Fuchs, Stijn N R
AU - Menzel, Sylvia
AU - Ziegler, Susanne
AU - Kröger, Nicolaus
AU - Triviai, Ioanna
AU - Büsche, Guntram
AU - Kreipe, Hans
AU - Banjanin, Bella
AU - Pritchard, Jessica E
AU - Hoogenboezem, Remco
AU - Bindels, Eric M
AU - Schumacher, Neele
AU - Rose-John, Stefan
AU - Elf, Shannon
AU - Saez-Rodriguez, Julio
AU - Kramann, Rafael
AU - Schneider, Rebekka K
N1 - © 2020 by The American Society of Hematology.
PY - 2020/10/29
Y1 - 2020/10/29
N2 - Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the pathogenesis of PMF have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in patients with MPN, we determined that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis. We show that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis, and decreases the activation of profibrotic pathways in megakaryocytes, inflammation in fibrosis-driving cells, and JAK/STAT activation in both megakaryocytes and stromal cells in 3 murine PMF models. Our data indicate that higher CXCL4 expression in MPN has profibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.
AB - Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) that leads to progressive bone marrow (BM) fibrosis. Although the cellular mutations involved in the pathogenesis of PMF have been extensively investigated, the sequential events that drive stromal activation and fibrosis by hematopoietic-stromal cross-talk remain elusive. Using an unbiased approach and validation in patients with MPN, we determined that the differential spatial expression of the chemokine CXCL4/platelet factor-4 marks the progression of fibrosis. We show that the absence of hematopoietic CXCL4 ameliorates the MPN phenotype, reduces stromal cell activation and BM fibrosis, and decreases the activation of profibrotic pathways in megakaryocytes, inflammation in fibrosis-driving cells, and JAK/STAT activation in both megakaryocytes and stromal cells in 3 murine PMF models. Our data indicate that higher CXCL4 expression in MPN has profibrotic effects and is a mediator of the characteristic inflammation. Therefore, targeting CXCL4 might be a promising strategy to reduce inflammation in PMF.
U2 - 10.1182/blood.2019004095
DO - 10.1182/blood.2019004095
M3 - SCORING: Journal article
C2 - 32726410
VL - 136
SP - 2051
EP - 2064
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 18
ER -
