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Published on: October 31, 2012
Despite differential gene expression profiles pediatric MDS derived mesenchymal stromal cells display functionality
F G J Calkoen1, C Vervat1, M van Pel2
1Department of Pediatrics, Section Immunology, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Leiden University Medical Center, Leiden, The Netherlands.
Abstract:
Pediatric myelodysplastic syndrome (MDS) is a heterogeneous disease covering a spectrum ranging from aplasia (RCC) to myeloproliferation (RAEB(t)). In adult-type MDS there is increasing evidence for abnormal function of the bone-marrow microenvironment. Here, we extensively studied the mesenchymal stromal cells (MSCs) derived from children with MDS. MSCs were expanded from the bone-marrow of 17 MDS patients (RCC: n=10 and advanced MDS: n=7) and pediatric controls (n=10). No differences were observed with respect to phenotype, differentiation capacity, immunomodulatory capacity or hematopoietic support. mRNA expression analysis by Deep-SAGE revealed increased IL-6 expression in RCC- and RAEB(t)-MDS. RCC-MDS MSC expressed increased levels of DKK3, a protein associated with decreased apoptosis. RAEB(t)-MDS revealed increased CRLF1 and decreased DAPK1 expressions. This pattern has been associated with transformation in hematopoietic malignancies. Genes reported to be differentially expressed in adult MDS-MSC did not differ between MSC of pediatric MDS and controls. An altered mRNA expression profile, associated with cell survival and malignant transformation, of MSC derived from children with MDS strengthens the hypothesis that the micro-environment is of importance in this disease. Our data support the understanding that pediatric and adult MDS are two different diseases. Further evaluation of the pathways involved might reveal additional therapy targets.
Insights
Pediatric myelodysplastic syndromes (MDS) involve altered bone marrow microenvironments. Mesenchymal stromal cells from children with MDS show distinct mRNA expression linked to cell survival and malignant transformation.
Area of Science:
- Hematology
- Oncology
- Cell Biology
Background:
- Pediatric myelodysplastic syndrome (MDS) is a heterogeneous clonal hematopoietic stem cell disorder.
- Evidence suggests the bone marrow microenvironment plays a role in adult MDS.
- The role of mesenchymal stromal cells (MSCs) in pediatric MDS remains less understood.
Purpose of the Study:
- To investigate the characteristics of bone marrow-derived MSCs from pediatric MDS patients.
- To compare MSCs from pediatric MDS patients with those from healthy pediatric controls.
- To identify molecular differences in MSCs that may contribute to pediatric MDS pathogenesis.
Main Methods:
- Expansion of MSCs from bone marrow of 17 pediatric MDS patients (10 with refractory cytopenia of childhood [RCC] and 7 with advanced MDS) and 10 pediatric controls.
- Assessment of MSC phenotype, differentiation capacity, immunomodulatory capacity, and hematopoietic support.
- Deep-SAGE mRNA expression analysis to identify differentially expressed genes.
Main Results:
- No significant differences in MSC phenotype, differentiation, immunomodulation, or hematopoietic support between pediatric MDS and control groups.
- Increased IL-6 expression observed in MSCs from RCC and RAEB(t)-MDS patients.
- RCC-MDS MSCs showed increased DKK3 expression; RAEB(t)-MDS MSCs exhibited increased CRLF1 and decreased DAPK1 expression, patterns associated with malignant transformation.
Conclusions:
- Altered mRNA expression profiles in MSCs from pediatric MDS patients suggest a role for the microenvironment in disease pathogenesis.
- The molecular signatures in pediatric MDS MSCs differ from those reported in adult MDS MSCs, supporting distinct disease entities.
- Further investigation into these altered pathways may identify novel therapeutic targets for pediatric MDS.
