[Show abstract][Hide abstract] ABSTRACT: Myelodysplastic syndromes (MDS) are clonal disorders involving hematopoietic stem cells (HSC) characterized by ineffective hematopoiesis. In addition to HSC defects, a defective hematopoiesis supporting capacity of mesenchymal stromal cells (MSC) in the microenvironment niche has been implicated in MDS pathophysiology. The interaction between the dysfunctional MSC MDS and HSC regulates diverse adhesion-related processes, such as progenitor cell survival, proliferation, differentiation and self-renewal. As previously reported, a microarray analysis identified SPINT2, an inhibitor of HGF activation, to be downregulated in MSC from MDS patients. To define the role of SPINT2 in MDS hematopoietic microenvironment, an analysis of the effect of SPINT2 silencing in MSC was carried out. We herein reported significantly lower levels of SPINT2 whereas HGF was expressed at higher levels in MSC from MDS patients compared to healthy controls. SPINT2 underexpression results in an increased expression, production and secretion of HGF and SDF-1 by MSC. An increased adhesion of normal HSC or malignant cells onto mesenchymal stromal cells silenced for SPINT2 was also observed. The altered MSC adhesion in SPINT2 knockdown cells was correlated with increased CD49b and CD49d expressions and with a decrease in CD49e expression. Our results suggest that the SPINT2 underexpression in the mesenchymal stromal cells from MDS patients is probably involved in the adhesion of progenitors to the bone marrow niche, through an increased HGF and SDF-1 signaling pathway.
Full-text · Article · Jan 2014 · Stem cells and development
[Show abstract][Hide abstract] ABSTRACT: The human FMNL1 is expressed predominantly in hematopoietic cells and has been described previously as overexpressed in hematopoietic malignancies. However, it is not known whether FMNL1 contributes to leukemogenesis. Here, we investigate the FMNL1 function using two different human leukemia models: Namalwa and K562 cell lines. FMNL1 depletion reduced cell proliferation and colony formation in both leukemic cell types, as well as a decrease in the tumor growth of FMNL1-depleted Namalwa cell xenografts. In addition, there was a decrease in migration and in TEM in FMNL1-depleted Namalwa cells. FMNL1 endogenously associates with Rac1, and FMNL1 silencing resulted in an increased Rac1 activity. The reduced migration observed in FMNL1-depleted cells was restored by inhibiting Rac activity. Our results indicate that FMNL1 stimulates leukemia cell proliferation as well as migration. This suggests that FMNL1 contributes to leukemogenesis and could act in part through Rac1 regulation.
Full-text · Article · Jun 2013 · Journal of leukocyte biology
[Show abstract][Hide abstract] ABSTRACT: The role of the immune system in myelodysplastic syndrome (MDS) progression has been widely accepted, although mechanisms underlying this immune dysfunction are not clear. CD4+ and CD8+ lymphocyte profiles in the peripheral blood of MDS patients were evaluated and correlated with clinical characteristics, the expression of FOXP3 and the anti-inflammatory cytokines IL10, TGFβ1 and CTLA4. IL10 expression inversely correlated with the percentage of CD8+ cells and was higher in high-risk MDS. Our findings provide further evidence for the role of T cell-mediated IL10 production in MDS and strengthen the idea of distinct cytokine profiles in low and high-risk MDS.
Full-text · Article · Feb 2013 · Leukemia research
[Show abstract][Hide abstract] ABSTRACT: Recent studies have indicated the Musashi2/NUMB pathway as the key regulator of differentiation in chronic myeloid leukemia; however, a comparison of both gene expressions has not yet been made in myelodysplastic syndrome (MDS) and in acute myeloid leukemia (AML). We herein, demonstrate a statistically significant down-modulation of NUMB expression level in high-risk MDS and AML, compared with control individuals. MSI2 expression was significantly reduced in low and high-risk MDS compared with normal control samples. NUMB expression was significantly lower than that of MSI2 in both MDS and AML patient samples, but no differences in the expression levels for either gene were observed in healthy bone marrow cells. Finally, NUMB expression was significantly up-regulated during differentiation of normal and low-risk MDS CD34(+) cells through the erythroid lineage. Taken together, results suggest the involvement of NUMB in MDS erythropoiesis; its down-modulation may have a role in MDS progression.
Full-text · Article · Jul 2012 · Leukemia research