Increased CXCL4 expression in hematopoietic cells links inflammation and progression of bone marrow fibrosis in MPN.

Abstract:

: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.

journal_name

Blood

journal_title

Blood

authors

Gleitz HFE,Dugourd AJF,Leimkühler NB,Snoeren IAM,Fuchs SNR,Menzel S,Ziegler S,Kröger N,Triviai I,Büsche G,Kreipe H,Banjanin B,Pritchard JE,Hoogenboezem R,Bindels EM,Schumacher N,Rose-John S,Elf S,Saez-Rodriguez J,Kr

doi

10.1182/blood.2019004095

subject

Has Abstract

pub_date

2020-10-29 00:00:00

pages

2051-2064

issue

18

eissn

0006-4971

issn

1528-0020

pii

461599

journal_volume

136

pub_type

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