Evaluation of Cytokines Mobilizing Hematopoietic Progenitor Cells in Patients with Myelofibrosis with Myeloid Metaplasia (MMM).

We have previously shown that in patients with MMM the number of circulating hematopoietic and endothelial progenitor cells is increased compared to other Ph-negative myeloproliferative disorders (Ph-CMPD). The aim of this study was to investigate the relevance of cytokines involved in the mobilization of progenitor cells from bone marrow to peripheral blood. We studied 120 patients with MMM, 22 patients with other Ph-CMPDs, and 30 healthy subjects. We evaluated by ELISA the plasma levels of stem cell factor (SCF), vascular endothelial growth factor (VEGF), and stromal derived factor-1alpha (SDF-1a). Moreover, the percentage of circulating CD34⁺ cells co-expressing the cytokine receptors CD117, VEGFR-2, or CXCR4 (for SCF, VEGF and SDF-1a, respectively) were assayed by flow cytometry. In all patients and controls, the percentage of circulating hematopoietic CD45⁺CD34⁺ cells and CD34⁺CD133⁺VEGFR-2⁺ endothelial progenitor cells were evaluated. SCF (median 872 pg/ml, range 281–2000), VEGF (median 38.9 pg/ml, range <15.6–2000), and SDF-1a (median, 3879 pg/ml, range <1560–18118) plasma levels were significantly higher (p<0.05, p<0.002, p<0.001, respectively) in patients with MMM than in normal controls (SCF, median 742 pg/ml, range 461–1167; VEGF, median <15.6 pg/ml, range <15.6–605; SDF-1a, median 1880 pg/ml, range <1560–8919). SDF-1a plasma levels of patients with MMM were also significantly higher (p<0.001) than those in other Ph-CMPDs (median 2896 pg/ml; range <1560–14144). In patients with MMM, cytokine plasma levels correlate with neither the percentage of CD34⁺ cells expressing their receptors, nor the percentage of circulating hemopoietic or endothelial progenitor cells. When clinical parameters were tested, we found a significant correlation between SDF-1a plasma levels and both the spleen size (n=113, R=0.20, p<0.05), and the number of immature myeloid cells (n=87, R=0.23, p<0.03). These data show increased plasma levels of SCF, VEGF, and SDF-1a in patients with MMM compared to normal controls; however, only SDF-1a characterizes patients with MMM with respect to those with other Ph-CMPDs. Neither the plasma levels of SDF-1a nor those of the other measured cytokines correlated with the extent of progenitor cells mobilization.