Mesenchymal stromal cells derived from the bone marrow of acute lymphoblastic leukemia patients show altered BMP4 production: correlations with the course of disease

PLoS One. 2014 Jan 6;9(1):e84496. doi: 10.1371/journal.pone.0084496. eCollection 2014.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Antigens, CD34 / metabolism
  • Bone Morphogenetic Protein 4 / biosynthesis*
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Proliferation
  • Cell Survival
  • Child
  • Child, Preschool
  • Coculture Techniques
  • Disease Progression
  • Female
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Immunophenotyping
  • Infant
  • Male
  • Mesenchymal Stem Cells / cytology
  • Mesenchymal Stem Cells / metabolism*
  • Neoplasm Staging
  • Neoplastic Stem Cells / metabolism
  • Phenotype
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / metabolism*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / pathology
  • Signal Transduction

Substances

  • Antigens, CD34
  • Bone Morphogenetic Protein 4

Grants and funding

This work was supported by grands BFU2009-10315, SAF2012-33180, and BFU2010-18250 from the Spanish Ministry of Science and Innovation, Spanish Association Against Cancer 2010 AECC; P2010/BMD-2420-CellCAM from Regional Government of Madrid and RD12/0019/0007-TerCell Network from the Health Institute Carlos III. MNVG contract UCM number 50053735 by Comunidad de Madrid. AE grant number AP2010-0795 of Ministry of Education, Culture and Sports. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.