title: Gene-expression and in vitro function of mesenchymal stromal cells are affected in juvenile myelomonocytic leukemia.
abstract: An aberrant interaction between hematopoietic stem cells and mesenchymal stromal cells has been linked to disease and shown to contribute to the pathophysiology of hematologic malignancies in murine models. Juvenile myelomonocytic leukemia is an aggressive malignant disease affecting young infants. Here we investigated the impact of juvenile myelomonocytic leukemia on mesenchymal stromal cells. Mesenchymal stromal cells were expanded from bone marrow samples of patients at diagnosis (n=9) and after hematopoietic stem cell transplantation (n=7; from 5 patients) and from healthy children (n=10). Cells were characterized by phenotyping, differentiation, gene expression analysis (of controls and samples obtained at diagnosis) and in vitro functional studies assessing immunomodulation and hematopoietic support. Mesenchymal stromal cells from patients did not differ from controls in differentiation capacity nor did they differ in their capacity to support in vitro hematopoiesis. Deep-SAGE sequencing revealed differential mRNA expression in patient-derived samples, including genes encoding proteins involved in immunomodulation and cell-cell interaction. Selected gene expression normalized during remission after successful hematopoietic stem cell transplantation. Whereas natural killer cell activation and peripheral blood mononuclear cell proliferation were not differentially affected, the suppressive effect on monocyte to dendritic cell differentiation was increased by mesenchymal stromal cells obtained at diagnosis, but not at time of remission. This study shows that active juvenile myelomonocytic leukemia affects the immune response-related gene expression and function of mesenchymal stromal cells. In contrast, the differential gene expression of hematopoiesis-related genes could not be supported by functional data. Decreased immune surveillance might contribute to the therapy resistance and progression in juvenile myelomonocytic leukemia.
authors: Department of Pediatrics, Immunology, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Leiden University Medical Center, the Netherlands f.g.j.calkoen@lumc.nl.
authors: Friso G J
authors: FG
authors: Calkoen
authors: Department of Pediatrics, Immunology, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Leiden University Medical Center, the Netherlands.
authors: Carly
authors: C
authors: Vervat
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors: Else
authors: E
authors: Eising
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors: Lisanne S
authors: LS
authors: Vijfhuizen
authors: Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
authors: Peter-Bram A C
authors: PB
authors: 't Hoen
authors: Dutch Childhood Oncology Group (DCOG), The Hague, the Netherlands Princess Maxima Center for Pediatric Oncology, Utrecht, the Netherlands.
authors: Marry M
authors: MM
authors: van den Heuvel-Eibrink
authors: Department of Pediatrics, Immunology, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Leiden University Medical Center, the Netherlands Department of Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Hospital for Sick Children, University of Toronto, ON, Canada.
authors: R Maarten
authors: RM
authors: Egeler
authors: Department of Pediatrics, Immunology, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Leiden University Medical Center, the Netherlands.
authors: Maarten J D
authors: MJ
authors: van Tol
authors: Department of Pediatrics, Immunology, Hematology/Oncology and Hematopoietic Stem Cell Transplantation, Leiden University Medical Center, the Netherlands.
authors: Lynne M
authors: LM
authors: Ball
mesh_terms: D002478:Cells, Cultured; D002675:Child, Preschool; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D006410:Hematopoiesis; D006801:Humans; D007223:Infant; D054429:Leukemia, Myelomonocytic, Juvenile / Q000378:metabolism* / Q000473:pathology; D008297:Male; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000473:pathology