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Targeting of the bone marrow microenvironment improves outcome in a murine model of myelodysplastic syndrome

Sophia R. Balderman, Allison J. Li, Corey M. Hoffman, Benjamin J. Frisch, Alexandra N. Goodman, Mark W. LaMere, Mary A. Georger, Andrew G. Evans, Jane L. Liesveld, Michael W. Becker and Laura M. Calvi

Key points

  • An in vivo model of MDS displays time-dependent defects in hematopoietic stem and progenitor cells and in microenvironmental populations.

  • Normalization of the marrow microenvironment alters disease progression and transformation and improves hematopoietic function.

Abstract

In vitro evidence suggests that the bone marrow microenvironment (BMME) is altered in the myelodysplastic syndromes (MDS). 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, while megakaryocytes were decreased. Both CCL3 and VEGF, 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 to 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.

  • Submitted June 24, 2015.
  • Accepted November 10, 2015.