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Roversi, Fernanda Marconi; Cury, Nathalia Moreno; Lopes, Matheus Rodrigues; Ferro, Karla Priscila; Machado‐Neto, João Agostinho; Alvarez, Marisa Claudia; dos Santos, Gabriela Pereira; Giardini Rosa, Renata; Longhini, Ana Leda; Duarte, Adriana da Silva Santos; Pericole, Fernando Vieira; Favaro, Patricia; Yunes, José Andres; Saad, Sara Teresinha Olalla
Journal of cellular and molecular medicine, 02/2019, Letnik: 23, Številka: 2Journal Article
Abstract The role of tumour microenvironment in neoplasm initiation and malignant evolution has been increasingly recognized. However, the bone marrow mesenchymal stromal cell ( BMMSC ) contribution to disease progression remains poorly explored. We previously reported that the expression of serine protease inhibitor kunitz‐type2 ( SPINT 2/ HAI ‐2), an inhibitor of hepatocyte growth factor ( HGF ) activation, is significantly lower in BMMSC from myelodysplastic syndromes ( MDS ) patients compared to healthy donors ( HD ). Thus, to investigate whether this loss of expression was due to SPINT 2/ HAI ‐2 methylation, BMMSC from MDS and de novo acute myeloid leukaemia (de novo AML ) patients were treated with 5‐Azacitidine (Aza), a DNA methyltransferase inhibitor. In MDS ‐ and de novo AML ‐ BMMSC , Aza treatment resulted in a pronounced SPINT 2/ HAI ‐2 levels up‐regulation. Moreover, Aza treatment of HD ‐ BMMSC did not improve SPINT 2/ HAI ‐2 levels. To understand the role of SPINT 2/ HAI ‐2 down‐regulation in BMMSC physiology, SPINT 2/ HAI ‐2 expression was inhibited by lentivirus. SPINT 2 underexpression resulted in an increased production of HGF by HS ‐5 stromal cells and improved survival of CD 34 + de novo AML cells. We also observed an increased adhesion of de novo AML hematopoietic cells to SPINT 2/ HAI ‐2 silenced cells. Interestingly, BMMSC isolated from MDS and de novo AML patients had increased expression of the integrins CD 49b, CD 49d, and CD 49e. Thus, SPINT 2/ HAI ‐2 may contribute to functional and morphological abnormalities of the microenvironment niche and to stem/progenitor cancer cell progression. Hence, down‐regulation in SPINT 2/ HAI ‐2 gene expression, due to methylation in MDS ‐ BMMSC and de novo AML ‐ BMMSC , provides novel insights into the pathogenic role of the leukemic bone marrow microenvironment.
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in: SICRIS
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