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| Author(s): |
Matheus Rodrigues Lopes
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Campinas, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Médicas |
| Defense date: | 2016-03-06 |
| Examining board members: |
Patricia Maria Bergamo Favaro;
Katia Borgia Barbosa Pagnano;
Marina Pereira Colella;
Fernando Luiz Affonso Fonseca;
Wagner Luiz Batista
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| Advisor: | Patricia Maria Bergamo Favaro; Sara Teresinha Olalla Saad |
| Abstract | |
Accumulating evidence has suggested an interaction between bone marrow microenvironment and malignant hematopoietic cells, which could result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemias (AML), among other effects. Therefore, understanding how the bone marrow microenvironment directly contributes to the pathogenesis of these diseases is important for the development of targeted therapy. We herein, characterized the changes in cytokine and inflammatory molecule expression changes and the function of mesenchymal stromal cells (MSC) from the bone marrow of patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. In addition, we studied the biological function of IL-32 in stromal cell line HS5 and characterized its the expression of IL-32 in CD3+ cells from the peripheral blood of MDS patients. We observed a significant inhibitory effect of MDS-MSC on Tlymphocyte proliferation, similar to that of control cells, followed by no significant differences in any of the cytokines tested. Both AML-MSC were able to significantly inhibit T-cell proliferation, however only at very low MSC/T cell ratios. When compared to the control, AMLMRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, SDF1, RPGE2, IDO, IL1?, IL6 and IL32, followed by a decrease in IL10 expression. Our data suggest that MSCs derived from MDS are not the main factor responsible for the altered immune response observed in some groups of MDS patients. In addition, the MSC derived from patients with AML-MRC presented a minor role in the maintenance of leukemic niche, whereas the MSCs derived from de novo AML, at least at an early stage of disease before any treatment, promoted a permissive niche for leukemogenesis, instead of the normal hematopoieses. We also showed that IL32 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 IL-32 participates in the regulation of the cytokine network in the bone marrow, at least in part, by signaling MAPK and NF-kB. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL32 participates in the regulation of the bone marrow cytokine milieu (AU) | |
| FAPESP's process: | 12/13068-0 - The role of IL32 in the immunemodulation of mesenchymal stem cell and the stromal-hematopoietic interection in myelodysplastic syndrome |
| Grantee: | Matheus Rodrigues Lopes |
| Support Opportunities: | Scholarships in Brazil - Doctorate |