title: Mesenchymal stromal cells derived from the bone marrow of acute lymphoblastic leukemia patients show altered BMP4 production: correlations with the course of disease.
abstract: The relevance of tumor microenvironment for the development and progression of tumor cells in hematological malignancies has been extensively reported. Identification of factors involved in the information exchange between the malignant cells and the bone marrow mesenchymal stem cells (BM-MSCs) and the knowledge on their functioning may provide important information to eliminate leukemic cells from protective BM niches. We evaluated changes in BM-MSCs obtained from children with acute lymphoblastic leukemia (ALL) at different times in the course of disease. Whereas ALL-MSCs did not exhibit phenotypic changes compared to BM-derived MSCs isolated from healthy donors, they exhibited increased adipogenic capacity. In addition, the viability of healthy CD34+ hematopoietic progenitors was significantly reduced when co-cultured with ALL-MSCs. ALL-MSCs grow less efficiently, although gradually recover normal growth with treatment. Accordingly, proliferation is particularly low in MSCs obtained at diagnosis and in the first days of treatment (+15 days), recovering to control levels after 35 days of treatment. Correlating these results with bone morphogenetic protein 4 (BMP4) production, a molecule demonstrated to affect MSC biology, we found higher production of BMP4 in ALL-MSCs derived from patients over the course of disease but not in those free of leukemia. However, no significant differences in the expression of different members of the BMP4 signaling pathway were observed. Furthermore, an inverse correlation between high levels of BMP4 production in the cultures and MSC proliferation was found, as observed in MSCs derived from patients at diagnosis that produce high BMP4 levels. In addition, co-culturing ALL-MSC with the REH leukemia cell line, but not CD34+ hematopoietic progenitors, powerfully enhanced BMP4 production, suggesting an intimate crosstalk among ALL-MSCs isolated from BM colonized by ALL cells that presumably also occurs in situ conditions. Our data may support the participation of BMP4 in BM niche, but the mechanism remains to be elucidated.
authors.affiliation: Department of Cell Biology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Vicente López
authors.affiliation: Department of Cell Biology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Miriam Nohemí
authors.initials: MN
authors.lastname: Vázquez García
authors.affiliation: Department of Oncohematology, Hospital Niño Jesús, Madrid, Spain.
authors.forename: Gustavo J
authors.initials: GJ
authors.lastname: Melen
authors.affiliation: Department of Cell Biology, School of Medicine, Complutense University, Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Entrena Martínez
authors.affiliation: Cellular Biotechnology Unit, Institute for Health Carlos III, Majadahonda, Madrid, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Cubillo Moreno
authors.affiliation: Cellular Biotechnology Unit, Institute for Health Carlos III, Majadahonda, Madrid, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: García-Castro
authors.affiliation: Department of Oncohematology, Hospital Niño Jesús, Madrid, Spain.
authors.forename: Manuel Ramírez
authors.initials: MR
authors.lastname: Orellana
authors.affiliation: Department of Cell Biology, Faculty of Biology, Complutense University, Madrid, Spain.
authors.forename: Agustín Gregorio Zapata
authors.initials: AG
authors.lastname: González
mesh_terms: D000293:Adolescent; D018952:Antigens, CD34 / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000096:biosynthesis*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002648:Child; D002675:Child, Preschool; D018920:Coculture Techniques; D018450:Disease Progression; D005260:Female; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism*; D009367:Neoplasm Staging; D014411:Neoplastic Stem Cells / Q000378:metabolism; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D018952:Antigens, CD34; D055415:Bone Morphogenetic Protein 4