Biology of BM failure syndromes: role of microenvironment and niches

Balderman, Sophia R.; Calvi, Laura M.

doi:10.1182/asheducation-2014.1.71

Cited by 29 publications

(23 citation statements)

References 81 publications

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“…31 Moreover, there is evidence from a murine model that a BMME defect can initiate MDS, suggesting that the BMME can also contribute to disease pathogenesis. 32 Xenotransplantation experiments in mice have shown enhancement of engraftment of HSCs from patients with MDS when they were coinjected with BMME cells, indicating that these HSCs are dependent on signals from the BMME.…”

Section: Discussionmentioning

confidence: 99%

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

Balderman¹,

Li²,

Hoffman

et al. 2016

Blood

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• 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)

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Section: Discussionmentioning

confidence: 99%

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

Balderman¹,

Li²,

Hoffman

et al. 2016

Blood

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“…The impact of the osteoblastic microenvironment has been studied not only in the steady state but also under ‘stress’ conditions, such as in patients with haematological disorders. Defects in BM stromal cells can be initiating steps in the pathogenesis of BM failure syndromes such as aplastic anaemia and myelodysplastic syndrome (MDS) . In addition, increased osteocalcin levels have been associated with abnormal and ineffective haematopoiesis in subjects with MDS, a clonal stem cell disorder characterized by impaired blood cell production and supply to the circulation.…”

Section: Discussionmentioning

confidence: 99%

High plasma osteocalcin is associated with low blood haemoglobin in elderly men: the MrOS Sweden Study

et al. 2016

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“…Much data from both murine models and primary human samples suggest a role for bone marrow stromal cell populations in the pathogenesis of MDS [106][107][108] (also reviewed in Balderman and Calvi 109 and Bulycheva et al 110 )…”

Section: Myelodysplastic Syndromesmentioning

confidence: 99%

The hematopoietic stem cell niche in homeostasis and disease

Calvi

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2015

Blood

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The bone marrow microenvironment contains a heterogeneous population of stromal cells organized into niches that support hematopoietic stem cells (HSCs) and other lineage-committed hematopoietic progenitors. The stem cell niche generates signals that regulate HSC self-renewal, quiescence, and differentiation. Here, we review recent studies that highlight the heterogeneity of the stromal cells that comprise stem cell niches and the complexity of the signals that they generate. We highlight emerging data that stem cell niches in the bone marrow are not static but instead are responsive to environmental stimuli. Finally, we review recent data showing that hematopoietic niches are altered in certain hematopoietic malignancies, and we discuss how these alterations might contribute to disease pathogenesis.

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Biology of BM failure syndromes: role of microenvironment and niches

Cited by 29 publications

References 81 publications

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

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

High plasma osteocalcin is associated with low blood haemoglobin in elderly men: the MrOS Sweden Study

The hematopoietic stem cell niche in homeostasis and disease

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