Open AccessUp‐regulation of SPINT 2/ HAI ‐2 by Azacytidine in bone marrow mesenchymal stromal cells affects leukemic stem cell survival and adhesion
Author(s) -
Roversi Fernanda Marconi,
Cury Nathalia Moreno,
Lopes Matheus Rodrigues,
Ferro Karla Priscila,
MachadoNeto João Agostinho,
Alvarez Marisa Claudia,
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
Publication year - 2019
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.14066
Subject(s) - stromal cell , biology , cancer research , haematopoiesis , bone marrow , progenitor cell , hepatocyte growth factor , stem cell , mesenchymal stem cell , myeloid , immunology , microbiology and biotechnology , genetics , receptor
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.