Altered SDF-1/CXCR4 axis in patients with primary myelofibrosis and in the Gata1low mouse model of the disease

Abstract

Objective-To assess whether alterations in the SDF-1/CXCR4 occur in patients with primary myelofibrosis (PMF) and in Gata1 low mice, an animal model for myelofibrosis, and whether these abnormalities might account for increased stem/progenitor cell trafficking.Materials and Methods-In the mouse, SDF-1 mRNA levels were assayed in liver, spleen and marrow. SDF-1 protein levels were quantified in plasma and marrow and CXCR4 mRNA and protein levels were evaluated on stem/progenitor cells and megakaryocytes purified from the marrow. SDF-1 protein levels were also evaluated in plasma and in marrow biopsy specimens obtained from normal donors and PMF patients.Results-In Gata1 low mice, the plasma SDF-1 protein was 5-times higher than normal in younger animals. Furthermore, SDF-1 immuno-staining of marrow sections progressively increased with age. Similar abnormalities were observed in PMF patients. In fact, the plasma SDF-1 levels in PMF patients were significantly higher (by 2-fold) than normal (p<0.01) and SDF-1 immuno-staining of marrow biopsiy specimens demonstrated increased SDF-1 deposition in specific areas. In two of the patients, SDF-1 deposition was normalized by curative therapy with allogenic stem cell transplantation. Similarly to what already has been reported for PMF patients, the marrow from Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Gata1 low mice contained fewer CXCR4 pos CD117 pos cells and these cells expressed low levels of CXCR4 mRNA and protein. NIH Public AccessConclusion-Similar abnormalities in the SDF-1/CXCR4 axis are observed in PMF patients and in the Gata1 low mice model of myelofibrosis. We suggest that these abnormalities contribute to the increased stem/progenitor cell trafficking observed in this mouse model as well as patients with PMF.

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

“…Significant downregulation of the chemokine stromal‐cell derived factor (SDF)‐1 (Cxcl12) was also observed, in line with previous studies characterizing niche cells in MPN 17, 34. Interestingly, deletion of Cxcl12 in stromal cells was shown to increase the number of circulating platelets 34, 55, and studies in patients with MF have suggested that the BM microenvironment is deprived of active Cxcl12 56. These data led to the hypothesis that Gli1 + stromal cells are activated from their niche by atypical platelets/megakaryocytes (mediated by Cxcl4), which leads to a cascade of myofibroblast transdifferentiation, metabolic reprogramming, and downregulation of Cxcl12.…”

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

“…Increase in CXCL12 serum levels have been observed in GATA-1 low mice, a phenotype consistent with the low GATA-1 levels observed in FAK KO HSCs 64 . On the other hand, CXCL12 serum increase was accompanied by elevated levels of its receptor CXCR4 in FAK KO PMNs sorted from lung after tumour cell injection.…”

Aberrant signal transduction pathways in myeloproliferative neoplasms

“…106 An altered SDF-1/CXCR4 axis was demonstrated in PMF patients with CD34( þ ) cells in the periphery. 107 These findings are supported by the rapid mobilization of CD34( þ ) cells with AMD3100, a CXCR4 antagonist. 108 Tyrosine phosphorylation pattern of JAK2 V617F JAK2 V617F is constitutively tyrosine phosphorylated.…”