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

Abstract

• An in vivo model of MDS displays time-dependent defects in HSPCs and in microenvironmental populations.• Normalization of the marrow microenvironment alters disease progression and transformation and improves hematopoietic function.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. (Blood. 2016;127(5):616-625)

The microenvironment in myelodysplastic syndromes: Niche-mediated disease initiation and progression

“…NHD13 mice exhibit pathologic features of human MDS evidenced by multi-lineage blood cytopenias, dyspoiesis of erythroid, megakaryocytic and granulocytic cells and progression to acute leukemia [84, 88]. In studies of the NHD13 model, MSCs and OBCs were increased in the BMME of 18–23 week old NHD13 mice [89]. However, NHD13 mice exhibited no changes in skeletal structure nor osteoblastic bone formation and osteoclastic bone resorption, indicating that the expanded populations do not generate functional bone-forming cells [89].…”

“…In studies of the NHD13 model, MSCs and OBCs were increased in the BMME of 18–23 week old NHD13 mice [89]. However, NHD13 mice exhibited no changes in skeletal structure nor osteoblastic bone formation and osteoclastic bone resorption, indicating that the expanded populations do not generate functional bone-forming cells [89]. Recently, Weidner et al reported decreased trabecular bone volume in younger NHD13 mice at 2 month of age when cytopenias are not yet prominent in this model [90].…”

“…Frisch et al found that osteoblastic inhibition in murine myeloid leukemia was associated with leukemic cell production of CCL3 (or MIP-1α), a chemokine previously reported as a mediator of osteoblastic dysfunction in multiple myeloma and chronic myelogenous leukemia (CML) [85, 92, 93]. Of note, CCL3 was also increased in NHD13 mice and in a cohort of patients with MDS [89, 94], suggesting that factors produced by MDS cells may drive mesenchymal-osteolineage abnormalities.…”

The microenvironment in human myeloid malignancies: emerging concepts and therapeutic implications

“…[106][107][108][109] Cytokine contribution to angiogenesis in non-BCR-ABL MPN has recently been reviewed elsewhere. 110 VEGF, for instance, is highly expressed by megakaryocytes, myeloid progenitors, and granulocytes in chronic and blast crisis CML, 111 with increased levels also observed in human 66,107 and mouse models of MDS, 112 where it appears to be equally secreted by malignant and stromal niche cells. EC activation by proinflammatory cytokines secreted by malignant cells (eg, TNFa, IL-6, and IL-1b) increases EC proliferation, EC expression of myeloid-promoting cytokines (G-CSF, granulocyte-macrophage-CSF [GM-CSF]) and might compromise vascular integrity.…”

Dynamic alterations of bone marrow cytokine landscape of myelodysplastic syndromes patients treated with 5-azacytidine

“…Besides cytogenetic, molecular and genetic abnormalities in hematopoietic stem cells (HSC), extrinsic factors such as interaction with immune system and bone marrow (BM) microenvironment alterations are involved not only in the BM failure, but also in clonal expansion of the aberrant HSC and impaired cellular differentiation. [1][2][3][4] There is growing evidence implicating inflammation-related changes, inhibitory cytokines and increased intramedullary apoptosis as contributors to ineffective hematopoiesis, specifically in the early stages of MDS. [5][6][7] Moreover, several recent studies implicate aberrant BM microenvironment and inflammation-related changes in progression of the MDS.…”