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Sci Rep
2017 Jan 13;7:40707. doi: 10.1038/srep40707.
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De novo AML exhibits greater microenvironment dysregulation compared to AML with myelodysplasia-related changes.
Lopes MR
,
Pereira JK
,
de Melo Campos P
,
Machado-Neto JA
,
Traina F
,
Saad ST
,
Favaro P
.
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The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.
Figure 2. Modulation of cytokines and molecules is mostly observed in the de novo AML group.qPCR analyses of mRNA expression of VEGFA (A), CXCL12 (B), TGFβ1 (C), RPGE2 (D), IDO (E), IL10 (F), IL1β (G), IL6 (H) and IL32 (I) in bone marrow MSC obtained from HC, MDS, AML-MRC and de novo AML patients. The “y” axis represents the relative mRNA expression. Horizontal lines indicate medians. The number of samples in each group and p values are indicated in the graph. Mann Whitney test.
Figure 3. Lentivirus-mediated miRNA efficiently silences IL-32 in HS5 cells and results in increasing of cell proliferation.Western blotting analyses of IL-32 expression for HS5 cells in the presence or not of TNF-α and IFN-γ (10 ng/mL) as indicated. The levels of IL-32 relative to actin were quantified. In the figures are reported the cropped gels/blots. All gels were run in the same experimental conditions (see material and methods for details). (Full-length blots are reported in Supplementary Figure S2). Results are shown relative to miControl cells, as mean ± SEM of three independent experiments. ANOVA, Bonferroni’s post-tests (**p < 0.01; ***p < 0.001). (C) Cell viability was determined by MTT assay after 48 hours of incubation of miIL32 (#1 and #2) and normalized by the corresponding miControl cells. Results are shown as mean ± SEM of four independent experiments; The MTT assay was performed in the presence or not of IFN-γ and TNF-α (10 ng/mL) as indicated. ANOVA, Bonferroni’s post-tests (*p < 0.05, **p < 0.01); (D) Ki-67 mean of fluorescence intensity (M.F.I.) was determined by flow cytrometry after incubation of miIL32 for 48 h and normalized by the corresponding miControl cells. The dotted line represents the mean of miControl cells. Results are shown as mean ± SEM of four independent experiments; **p < 0.01, Student t test.
Figure 6. IL-32 silencing down-modulates cytokines, MAPK and NF- κB signaling components in HS5 cells.(A,B) The fold-change in cytokine concentration in miIL32 HS5 cell supernatant compared to miControl cell values is plotted, in the presence or not of IFN-γ and TNF-α (10 ng/mL) as indicated. Results are shown as mean ± SEM of 3 independent experiments. (C) HS5 cells transduced either with miIL32#1 or miIL32#2 and miControl. Western blot for IL-32, p-NF-κB, p-IKKβ, and p-IKKα; (D) p-JNK and p-p38 MAPK. (E) Activation status of NF-κB signaling in AML-MSC patients; western blot for p-NF-κB in total protein of MSC cells. Gels were run under the same experimental conditions while images of western blots displayed in cropped format. Membranes were reprobed with antibodies against actin or total protein. Full-length blots/gels are presented in Supplementary Figure S3.
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