Involvement of transforming growth factor-β and thrombopoietin in the pathogenesis of myelodysplastic syndrome with myelofibrosis

Akiyama, Takehide; Matsunaga, Takuya; Terui, Takeshi; Miyanishi, Koji; Tanaka, Ikuta; Sato, Tsutomu; Kuroda, Hiroyuki; Takimoto, Rishu; Takayama, Tetsuji; Kato, Junji; Yamauchi, Naofumi; Kogawa, Katsuhisa; Sakamaki, Sumio; Hirayama, Yasuo; Kohda, Kyuhei; Niitsu, Yoshiro

doi:10.1038/sj.leu.2403875

Cited by 20 publications

(18 citation statements)

References 31 publications

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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. 26–28 Furthermore, it was previously shown that TGFβ1 at this concentration mediates pathophysiologically relevant effects in other myeloid malignancies such as AML, chronic myeloid leukemia and myeloproliferative syndromes.…”

Section: Methodssupporting

confidence: 51%

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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Section: Methodssupporting

confidence: 51%

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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“…Transforming growth factor-␤ (TGF-␤) is a myelosuppressive cytokine that has been implicated in the hematopoietic suppression in MDS. The plasma levels of TGF-␤ have been reported to be elevated in some [9][10][11][12][13] but not all studies [14][15][16][17] and are supported by greater TGF-␤ immunohistochemical staining in selected studies. In addition to direct myelosuppressive effects, TGF-␤ has also been implicated in the autocrine production of other myelosuppressive cytokines (TNF, IL-6, and IFN␥) in MDS.…”

Section: Introductionmentioning

confidence: 63%

“…Most reports to date have relied upon immunohistochemical detection of TGF-␤ in patient bone marrows or measurement of TGF-␤ levels in patient plasma. Some of these studies showed increased TGF-␤ in MDS, [10][11][12][13] whereas some did not observe any correlation. [14][15][16][17] As local concentrations of cytokines can be more informative than serum concentrations and immunohistochemical detection of cell surface proteins in bone marrow sections has technical limitations, we focused our studies on direct evaluation of nuclear smad2 phosphorylation in MDS bone marrows.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the TGF-β receptor I kinase promotes hematopoiesis in MDS

Zhou

Nguyen²,

Sohal

et al. 2008

Blood

162

121

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MDS is characterized by ineffective hema- IntroductionThe myelodysplastic syndromes (MDSs) are clonal stem cell disorders characterized by cytologic dysplasia and ineffective hematopoiesis. [1][2][3] Although approximately one third of patients may progress to acute leukemia, refractory cytopenias are the principal cause of morbidity and mortality in patients with MDS. 4 In fact, approximately two-thirds of patients present with lower risk disease characterized by hypercellular marrows with increased rates of apoptosis in the progenitor and differentiated cell compartments in the marrow. [5][6][7][8] Ineffective hematopoiesis arising from abortive maturation leads to peripheral cytopenias. Higher grade or more advanced disease categories are associated with a significant risk of leukemia transformation, with a corresponding lower apoptotic index and higher percentage of marrow blasts.Cytokines play important roles in the regulation of normal hematopoiesis, and a balance between the actions of hematopoietic growth factors and myelosuppressive factors is required for optimal production of different hematopoietic cell lineages. Excess production of inhibitory cytokines amplifies ineffective hematopoiesis inherent to the MDS clone. Transforming growth factor-␤ (TGF-␤) is a myelosuppressive cytokine that has been implicated in the hematopoietic suppression in MDS. The plasma levels of TGF-␤ have been reported to be elevated in some [9][10][11][12][13] but not all studies [14][15][16][17] and are supported by greater TGF-␤ immunohistochemical staining in selected studies. In addition to direct myelosuppressive effects, TGF-␤ has also been implicated in the autocrine production of other myelosuppressive cytokines (TNF, IL-6, and IFN␥) in MDS. 18 Conflicting data may arise from technical limitations of bone marrow immunohistochemical analyses of a secreted protein as well as the biologic heterogeneity of the disease itself. In addition, plasma levels of TGF-␤ may not be an accurate reflection of the biologic effects of this cytokine in the MDS bone marrow microenvironment. Thus we investigated the role of TGF-␤ in MDS by direct examination of receptor signal activation to conclusively determine its role in the pathogenesis of ineffective hematopoiesis in MDS.Our previous studies have shown that signaling pathways activated by myelosuppressive cytokines can serve as therapeutic targets in low-risk MDS. We showed that interferons (IFN␣, IFN␤, and IFN␥), TGF-␤, and tumor necrosis factor ␣ (TNF␣) can all activate the p38 mitogen-activated protein kinase (MAPK) in primary human hematopoietic progenitors and that activation of p38 is required for myelosuppressive actions of these cytokines on hematopoiesis. 19,20 We subsequently confirmed overactivation of p38 MAPK in the bone marrow progenitors of low-risk MDS patients. Our data showed that inhibition of this cytokinestimulated p38 MAPK pathway partially rescues hematopoiesis in MDS progenitors. This led to a clinical trial of a p38 inhibitor, SCIO-469, in low-risk MDS; the ...

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“…Transforming growth factor-beta (TGF-b) is a myelosuppressive cytokine that has been implicated in the hematopoietic suppression in MDS. The plasma levels of TGF-b have been reported to be elevated in some [9][10][11][12][13] but not all studies [14][15][16][17] and are supported by greater TGF-b immunohistochemical staining in selected studies. Conflicting data may arise from technical limitations of bone marrow immunohistochemical analyses of a secreted protein, as well as the biological heterogeneity of the disease itself.…”

Section: Introductionmentioning

confidence: 64%