Multiple myeloma–related deregulation of bone marrow–derived CD34+ hematopoietic stem and progenitor cells

Bruns, Ingmar; Cadeddu, Ron Patrick; Brueckmann, Ines; Fröbel, Julia; Geyh, Stefanie; Büst, Sebastian; Fischer, Johannes C.; Roels, Frederik; Wilk, C. Matthias; Schildberg, Frank A.; Hünerlitürkoglu, A; Zilkens, Christoph; Jäger, Markus; Steidl, Ulrich; Zohren, Fabian; Fenk, Roland; Kobbe, Guido; Brors, Benedikt; Czibere, Akos; Schroeder, Thomas; Trumpp, Andreas; Haas, Rainer

doi:10.1182/blood-2011-04-347484

Cited by 86 publications

(95 citation statements)

References 50 publications

(54 reference statements)

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“…13 Recent data have pointed to a reduction of BM megakaryocyte-erythrocyte precursors in MM patients and more generally to a functional impairment of migratory, adhesive and proliferative capacities of hematopoietic stem and progenitor cells, caused by TGF-beta and NFkB signaling alterations. 14 These results strengthen the relevance of the perturbation of BM microenvironment induced by MM PC and mesenchymal stromal cells.…”

Section: Introductionsupporting

confidence: 61%

Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma

et al. 2015

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Section: Introductionsupporting

confidence: 61%

Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma

et al. 2015

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“…21–23 The inhibitor was diluted in dimethyl sulfoxide (10 mM). The concentration of TGFβ1 used in our experiments is within the range of TGFβ1 levels previously detected in patients with MDS 24,25 and has demonstrated inhibitory effects on healthy and MDS-derived hematopoietic cells.…”

Section: Methodsmentioning

confidence: 99%

Transforming growth factor β1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia

et al. 2018

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Mesenchymal stromal cells are involved in the pathogenesis of myelodysplastic syndromes and acute myeloid leukemia, but the underlying mechanisms are incompletely understood. To further characterize the pathological phenotype we performed RNA sequencing of mesenchymal stromal cells from patients with myelodysplastic syndromes and acute myeloid leukemia and found a specific molecular signature of genes commonly deregulated in these disorders. Pathway analysis showed a strong enrichment of genes related to osteogenesis, senescence, inflammation and inhibitory cytokines, thereby reflecting the structural and functional deficits of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia on a molecular level. Further analysis identified transforming growth factor β1 as the most probable extrinsic trigger factor for this altered gene expression. Following exposure to transforming growth factor β1, healthy mesenchymal stromal cells developed functional deficits and adopted a phenotype reminiscent of that observed in patient-derived stromal cells. These suppressive effects of transforming growth factor β1 on stromal cell functionality were abrogated by SD-208, an established inhibitor of transforming growth factor β receptor signaling. Blockade of transforming growth factor β signaling by SD-208 also restored the osteogenic differentiation capacity of patient-derived stromal cells, thus confirming the role of transforming growth factor β1 in the bone marrow microenvironment of patients with myelodysplastic syndromes and acute myeloid leukemia. Our findings establish transforming growth factor β1 as a relevant trigger causing functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia and identify SD-208 as a candidate to revert these effects.

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“…Second, the source of CD34-positive cells used to quantify stromal function was a peripheral blood stem cell harvest from a patient with multiple myeloma. Since CD34-positive cells from such patients display transient functional abnormalities [44], our results may not be reproducible using CD34-positive cells from healthy individuals. Third, and most importantly, stromal function was assessed after prolonged in vitro culture.…”

Section: Discussionmentioning

confidence: 55%

Functional abnormalities and changes in gene expression in fibroblasts and macrophages from the bone marrow of patients with acute myeloid leukemia

Dürig

Göbel

et al. 2015

Int J Hematol

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In bone marrow malignancies, little is known about the fate of stromal cells after replacement of normal cells by neoplastic hematopoietic ones. In this study, fibroblasts from patients with acute myeloid leukemia or myelodysplastic syndromes exhibited a significantly lower ability to support hematopoiesis originating from co-cultured allogeneic CD34-positive cells than did fibroblasts from healthy marrow. Conversely, macrophages from acute myeloid leukemia marrow significantly enhanced the production of blood cells compared with control macrophages. Aberrant function was associated with consistent changes in the expression of genes involved in hematopoietic stem cell control, such as cytokines and regulators of the Wnt signaling pathway.

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Multiple myeloma–related deregulation of bone marrow–derived CD34+ hematopoietic stem and progenitor cells

Cited by 86 publications

References 50 publications

Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma

Erythroblast apoptosis and microenvironmental iron restriction trigger anemia in the VK*MYC model of multiple myeloma

Transforming growth factor β1-mediated functional inhibition of mesenchymal stromal cells in myelodysplastic syndromes and acute myeloid leukemia

Functional abnormalities and changes in gene expression in fibroblasts and macrophages from the bone marrow of patients with acute myeloid leukemia

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