Reduced Expression of CXCR4 on Circulating CD34+ Cells Is Associated with Hematopoietic Progenitor Cells (HPC) Mobilization in Patients with Myelofibrosis with Myeloid Metaplasia (MMM).

Abstract

Abstract Spontaneous mobilization of HPC is a key feature of MMM. We investigated the CXCR4/SDF-1 (stromal derived factor-1) axis in 52 consecutive MMM patients. The percentage of circulating CD34+ cells co-expressing CXCR4 at the cytofluorimetric analysis was significantly lower (P=0.02) in MMM patients (median, 37%, range, 0 to 92%) than in the normal controls (n=12; median, 75%; range, 39 to 91%). CXCR4 mean fluorescence intensity was also highly significantly lower in MMM patients (median 0.73; range, 0.06 to 7.05) than in normal controls (median, 1.84; range, 0.41 to 6.69; P=0.004). By analyzing the association between CXCR4 expression and the mobilization of progenitor cells, an inverse correlation was found between CXCR4 expression and the number of circulating CD45+/CD34+ HPC (R=−0.40; P=0.005). By restricting the relation analysis of CXCR4 expression and clinical features to those patients who were not receiving cytoreductive treatment (n=41), there was no correlation between CXCR4 expression and patients’ sex, hemoglobin concentration, WBC, prefibrotic stage. By contrast, CXCR4 expression was inversely correlated with clinical characteristics that portrayed an advanced disease, such as older age (R=−0.31; P=0.026), longer disease duration (R=−0.37; P=0.008), larger splenomegaly (r=−0.33; P=0.015) and lower platelet count (r=0.42; P=0.007). The levels of CXCR4 mRNA, measured in peripheral blood CD34+ cells of patients with MMM were lower as compared with those of cells purified from normal peripheral blood (ΔCT by real time RT-PCR using GAPDH as housekeeping reference gene: 5.33 ± 0.49 vs. 1.53 ± 0.79, mean ± SD; P=0.003). SDF-1 plasma levels were significantly increased in patients with MMM but no correlation was documented with CXCR4 expression. We conclude that reduced expression of CXCR4 on CD34+ cells is a mechanism for the constitutive mobilization of HPC in MMM.