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Editorials
Figure 1. Platelet-derived growth factor (PDGF) signaling in myelofibrosis. Previous (human) data and the study by Kramer et al.1 indicate that the ligands PDGF-A and PDGF-B and their receptors PDGFRa and PDGFRb play important roles in myelofibrosis development. PDGFRa is mainly expressed on megakaryocytes and can be activated by the dimeric ligands PDGF-AA, PDGF-AB, and PDGF-BB. PDGFRb is expressed on stromal cells and can be activated through the ligand PDGF-BB. PDGF- BB stimulates stromal cell proliferation, migration and differentiation, which in turn causes extracellular matrix deposition and myelofibrosis development.
Platelet-derived growth factor pathway as a potential biomarker for myelofibrosis development
Platelet-derived growth factors are growth factors for fibroblasts and stromal cells. Importantly, upregulation of the receptors PDGFRa in megakaryocytes and PDGFRb in stromal cells, as well as upregulation of their ligands PDGF-A and PDGF-B, has been shown in established human myelofibrosis.5-7 Moreover, the grade of myelofi- brosis in myeloid malignancies correlates with the level of PDGFRb expression in activated fibroblasts.6 These data suggest that PDGF signaling contributes to myelofibrosis development.
Myelofibrosis occurs in the context of megakaryocyte disorders, encompassing both inherited bleeding and platelet disorders8,9 and myeloid malignancies, most com- monly, myeloproliferative neoplasms (MPN). Although patients with MPN can present with de novo myelofibrosis (i.e. primary myelofibrosis, PMF), it can also occur as a complication of antecedent MPN (i.e. post-polycythemia myelofibrosis, PPV-MF or post-essential thrombo- cythemia myelofibrosis, PET-MF). In patients with PV and ET, it is currently difficult to predict who will progress to myelofibrosis. The study by Kramer et al. raises the ques-
tion of whether increased PDGF signaling could serve as an early biomarker for myelofibrosis development.
Bedekocivs et al.6 previously assessed PDGFRb expression in fibrotic and non-fibrotic BM from several myeloid malig- nancies and proposed that elevated PDGFRb expression could indicate a prefibrotic state. Kramer et al. found increased PDGFRa expression in the prefibrotic stage, but no increase in PDGFRb or the ligands PDGF-A and -B. In future studies, it would be informative to measure the dynamics of PDGF components in human myelofibrosis development, using a longitudinal study to determine their predictive and prognostic value.
Targeting the platelet-derived growth factor pathway
In conjunction with prior (human) studies, this study by Kramer et al. suggests that the PDGF pathway is a potential therapeutic target in myelofibrosis. PDGFR are one of the main targets of the tyrosine kinase inhibitor, imatinib.10 Treatment with imatinib has demonstrated clinical benefit in patients with hypereosinophilic syndromes and chronic myeloproliferative disorders who have chromosomal translocations involving PDGFRa and PDGFRb, respective- ly.11,12 Thrombopoietin (Thpo) is the major stimulant for
haematologica | 2020; 105(8)
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