Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome
Autor: | Allison J. Li, Alexandra N Goodman, Andrew G. Evans, Mark W. LaMere, Jane L. Liesveld, Sophia R. Balderman, Laura M. Calvi, Michael W. Becker, Mary A. Georger, Benjamin J. Frisch, Corey M. Hoffman |
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Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
medicine.medical_specialty Oncogene Proteins Fusion Immunology Mice Transgenic Biochemistry Mice 03 medical and health sciences chemistry.chemical_compound Bone Marrow hemic and lymphatic diseases medicine Animals Humans Transgenes Progenitor cell Homeodomain Proteins Myeloid Neoplasia business.industry Myelodysplastic syndromes Mesenchymal stem cell Cell Biology Hematology Hematopoietic Stem Cells medicine.disease Surgery Mice Inbred C57BL Nuclear Pore Complex Proteins Vascular endothelial growth factor Transplantation Disease Models Animal Leukemia Haematopoiesis 030104 developmental biology medicine.anatomical_structure Cellular Microenvironment chemistry Myelodysplastic Syndromes Cancer research Bone marrow business Transcription Factors |
Zdroj: | Blood. 127:616-625 |
ISSN: | 1528-0020 0006-4971 |
Popis: | In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in myelodysplastic syndromes (MDSs). Here, we study the BMME in MDS in vivo using a transgenic murine model of MDS with hematopoietic expression of the translocation product NUP98-HOXD13 (NHD13). This model exhibits a prolonged period of cytopenias prior to transformation to leukemia and is therefore ideal to interrogate the role of the BMME in MDS. In this model, hematopoietic stem and progenitor cells (HSPCs) were decreased in NHD13 mice by flow cytometric analysis. The reduction in the total phenotypic HSPC pool in NHD13 mice was confirmed functionally with transplantation assays. Marrow microenvironmental cellular components of the NHD13 BMME were found to be abnormal, including increases in endothelial cells and in dysfunctional mesenchymal and osteoblastic populations, whereas megakaryocytes were decreased. Both CC chemokine ligand 3 and vascular endothelial growth factor, previously shown to be increased in human MDS, were increased in NHD13 mice. To assess whether the BMME contributes to disease progression in NHD13 mice, we performed transplantation of NHD13 marrow into NHD13 mice or their wild-type (WT) littermates. WT recipients as compared with NHD13 recipients of NHD13 marrow had a lower rate of the combined outcome of progression to leukemia and death. Moreover, hematopoietic function was superior in a WT BMME as compared with an NHD13 BMME. Our data therefore demonstrate a contributory role of the BMME to disease progression in MDS and support a therapeutic strategy whereby manipulation of the MDS microenvironment may improve hematopoietic function and overall survival. |
Databáze: | OpenAIRE |
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