Myeloproliferative leukemia protein activation directly induces fibrocyte differentiation to cause myelofibrosis

Abstract

Myelofibrosis (MF) may be caused by various pathogenic mechanisms such as elevation in circulating cytokine levels, cellular interactions and genetic mutations. However, the underlying mechanism of MF still remains unknown. Recent studies have revealed that fibrocytes, the spindle-shaped fibroblast-like hematopoietic cells, and the thrombopoietin (TPO)/myeloproliferative leukemia protein (MPL; TPO receptor) signaling pathway play a certain role in the development of MF. In the present study, we aimed to investigate the relationship between fibrocytes and MPL activation. We showed that TPO or a TPO receptor agonist directly induces fibrocyte differentiation using murine fibrocyte cell lines and a murine MF model. Conversely, elimination of macrophages expressing MPL by clodronate liposomes reversed the MF phenotype of the murine model, suggesting that fibrocyte differentiation induced by MPL activation contributes to the progression of MF. Furthermore, we revealed that SLAMF7 MPL monocytes in human peripheral blood mononuclear cells were possible fibrocyte precursors and that these cells increased in number in MF patients not treated with ruxolitinib. Our findings confirmed a link between fibrocytes and the TPO/MPL signaling pathway, which could result in a greater understanding of the pathogenesis of MF and lead to the development of novel therapeutic interventions.

Immunoproteasome Genes Are Modulated in CD34+ JAK2V617F Mutated Cells from Primary Myelofibrosis Patients

“…Our analysis would suggest that, based on interaction with hematopoietic progenitors, CD8 T cells are more active in patients with PMF. This is in line with the clinical observation that hematopoietic progenitors could respond to chronic inflammation in the context of a systemic autoimmune disease favoring fibroblast activation leading to bone marrow fibrosis and progressive cytopenias, in both primary and secondary myelofibrosis [63]. Moreover, we found that HLA class I genes expression levels were closely related to PMF disease and JAK2 V617F mutation, indicating a potential relationship with CD8 + T-cells [64].…”

Calreticulin del52 and ins5 knock-in mice recapitulate different myeloproliferative phenotypes observed in patients with MPN

“…As expected, stimulation of mu/hu MPL with TPO abolished the differences in STAT5 activation in presence of any of the CALR mutants and CALR wt. In order to verify whether the mild MF phenotype developed by del52/del52 KI mice was due to sub-optimal stimulation of mu MPL by the chim CALR del52 protein, we treated 1 month post-induction homozygous KI mice with the MPL agonist romiplostim, that was previously reported to induce MF in wt mice 15 . The romiplostim-treated homozygous del52 KI mice developed a significant BM hypocellularity and splenomegaly compared to treated wt littermates ( Fig.…”

Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma

“…82 Prospective data on the effects of dose interruptions, the optimal duration of the interruptions, and the efficacy and optimal dosing of TPO mimetics are lacking. Potential financial restrictions and the risks of thrombosis and myelofibrosis 95,96 should also be considered with these agents. TPO agonists require a minimum of 5 days to boost platelet production and reach maximum efficacy at w12 days.…”