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Involvement of MAF/SPP1 axis in the development of bone marrow fibrosis in PMF patients
S Ruberti1, E Bianchi1, P Guglielmelli2
1Department of Life Sciences, Centre for Regenerative Medicine 'Stefano Ferrari', University of Modena and Reggio Emilia, Modena, Italy.
Abstract:
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by hyperplastic megakaryopoiesis and myelofibrosis. We recently described the upregulation of MAF (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog) in PMF CD34+ hematopoietic progenitor cells (HPCs) compared to healthy donor. Here we demonstrated that MAF is also upregulated in PMF compared with the essential thrombocytemia (ET) and polycytemia vera (PV) HPCs. MAF overexpression and knockdown experiments shed some light into the role of MAF in PMF pathogenesis, by demonstrating that MAF favors the megakaryocyte and monocyte/macrophage commitment of HPCs and leads to the increased expression of proinflammatory and profibrotic mediators. Among them, we focused our further studies on SPP1 and LGALS3. We assessed SPP1 and LGALS3 protein levels in 115 PMF, 47 ET and 24 PV patients plasma samples and we found that SPP1 plasma levels are significantly higher in PMF compared with ET and PV patients. Furthermore, in vitro assays demonstrated that SPP1 promotes fibroblasts and mesenchymal stromal cells proliferation and collagen production. Strikingly, clinical correlation analyses uncovered that higher SPP1 plasma levels in PMF patients correlate with a more severe fibrosis degree and a shorter overall survival. Collectively our data unveil that MAF overexpression contributes to PMF pathogenesis by driving the deranged production of the profibrotic mediator SPP1.
Insights
MAF oncogene overexpression in primary myelofibrosis (PMF) drives abnormal cell development and elevates SPP1, a mediator of fibrosis. This finding links MAF to PMF progression and poorer patient survival.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Primary myelofibrosis (PMF) is a myeloproliferative neoplasm marked by abnormal megakaryocyte proliferation and bone marrow fibrosis.
- MAF (v-maf avian musculoaponeurotic fibrosarcoma oncogene homolog) was previously found to be upregulated in PMF CD34+ hematopoietic progenitor cells (HPCs).
Purpose of the Study:
- To investigate the role of MAF in PMF pathogenesis.
- To explore the relationship between MAF, its downstream mediators, and disease characteristics.
Main Methods:
- Comparative analysis of MAF expression in HPCs from PMF, essential thrombocytemia (ET), and polycythemia vera (PV) patients.
- MAF overexpression and knockdown experiments in vitro.
- Assessment of SPP1 and LGALS3 protein levels in patient plasma samples.
- In vitro assays on fibroblast and mesenchymal stromal cell proliferation and collagen production.
- Clinical correlation analysis of SPP1 levels with fibrosis severity and patient survival.
Main Results:
- MAF is upregulated in PMF HPCs compared to ET and PV HPCs.
- MAF promotes megakaryocyte and monocyte/macrophage commitment and increases proinflammatory/profibrotic mediators.
- SPP1 (secreted phosphoprotein 1) plasma levels are significantly higher in PMF patients.
- SPP1 promotes fibroblast and mesenchymal stromal cell proliferation and collagen production.
- Higher SPP1 levels correlate with increased fibrosis and reduced overall survival in PMF patients.
Conclusions:
- MAF overexpression contributes to PMF pathogenesis.
- MAF drives the production of the profibrotic mediator SPP1.
- SPP1 is a potential biomarker for PMF severity and prognosis.
