title: Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Sophia R
authors.initials: SR
authors.lastname: Balderman
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Physiology, and.
authors.forename: Corey M
authors.initials: CM
authors.lastname: Hoffman
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Frisch
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Goodman
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Mark W
authors.initials: MW
authors.lastname: LaMere
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
authors.forename: Mary A
authors.initials: MA
authors.lastname: Georger
authors.affiliation: Department of Pathology and Laboratory Medicine.
authors.forename: Andrew G
authors.initials: AG
authors.lastname: Evans
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Jane L
authors.initials: JL
authors.lastname: Liesveld
authors.affiliation: Division of Hematology/Oncology, Department of Medicine.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Becker
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY.
authors.forename: Laura M
authors.identifier: http://orcid.org/0000-0001-6969-239X
authors.initials: LM
authors.lastname: Calvi
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology*; D060833:Cellular Microenvironment; D004195:Disease Models, Animal; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000473:pathology*; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D019076:Transgenes
chemical_list: D018398:Homeodomain Proteins; C084118:Hoxd13 protein, mouse; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D014157:Transcription Factors; C093350:nuclear pore complex protein 98