Imbalance Between Apoptosis and Telomerase Activity in Myelodysplastic Syndromes: Possible Role in Ineffective Hemopoiesis

Ohshima, Koichi; Karube, Kennosuke; Shimazaki, Kae; Kamma, Hiroshi; Suzumiya, Junji; Hamasaki, Makoto; Kikuchi, Masahiro

doi:10.1080/1042819031000083037

Cited by 25 publications

(15 citation statements)

References 31 publications

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“…In the present study we tested both hTERT expression and telomerase activity in the same group of MDS patients and found that telomerase activity as well as hTERT expression were higher in MDS patients and AML/MDS than in controls, the increase being more pronounced in patients with more severe disease (RCMD, RAEB, AML), in agreement with the results reported by Oshima et al 36 However, the telomerase activity appeared to be Telomerae activities and the expression levels of hTERT mRNA in both controls and MDS patients were well correlated. The Spearman rank correlation was 0.524 and p = 0.0486. c-Myc, mad1 and p53 expression.…”

Section: Discussionsupporting

confidence: 81%

“…On the contrary Campbell et al 35 recently reported that hTERT is downregulated in the hematopoietic stem cells of patients with chronic myeloid leukaemia. Oshima K, et al 36 found that telomerase activity is higher in AML/MDS than in MDS and controls, whereas opposite results were reported by other authors 16 that did not find significant differences in telomerase activity in bone marrow of MDS patients compared to controls. It must be remarked that in literature data telomerase activity and hTERT expression were independently investigated by different groups in MDS patients, and this may account for some discrepancies in reported results.…”

Section: Discussioncontrasting

confidence: 48%

“…Low density bone marrow cells were separated on a ficoll-hypaque (Lymphoprep) gradient at 1077 g/l. Total RNA was isolated using the RNA fast Kit (Molecular System, Genenco, Milano, extremely variable in the different patients, and this observation may account for the different results reported by other authors 16 On the other hand, hTERT expression was found to be more homogeneously elevated in MDS patients, according to the results reported by Oshima et al 36 who showed that the percentage of hTERT-BM positive cells was higher in AML-MDS and MDS than in controls.…”

Section: Methodssupporting

confidence: 39%

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Increase of telomerase activity and hTERT expression in myelodysplastic syndromes

Briatore¹,

Barrera²,

Pizzimenti³

et al. 2009

Cancer Biology & Therapy

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Telomerase enzyme, containing a catalytic subunit, the human telomerase reverse transcriptase (hTERT), and a small integral RNA component, synthesises the telomeres, the ends of eukaryotic chromosomes. Inhibition of telomerase activity leads the cells to senescence and death. Myelodysplastic syndromes (MSD) are hematological malignancies characterized by peripheral blood cytopenia and ineffective hematopoiesis. Telomerase activity and hTERT expression in MDS patients were independently investigated by different groups obtaining contradictory results. We analyzed telomerase activity and hTERT expression in the bone marrow of ten control, 15 MDS patients and two patients with AML, likely evolved from a previous MDS. Moreover, the expression of c-myc, mad1, p53 (transcription factors involved in hTERT expression regulation), has been investigated. Telomerase activity and hTERT expression increased in the MDS patients with respect to the controls. The analysis of the MDS subgroups, indicated that patients with more severe disease demonstrated significantly higher levels of hTERT expression and telomerase activity with respect to the patients with more favorable disease. c-Myc and p53 expressions were not significantly different between controls and MDS patients, whereas mad1 expression was increased in MDS patiens, particularly in those with more favorable disease. We hypothesize that mad1 increase can contribute to reduce the hTERT expression in the early stage of disease and we suggest that hTERT expression and telomerase activity, whether confirmed in larger series of cases could support other parameters in the diagnosis and stadiation of MDS.

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Section: Discussionsupporting

confidence: 81%

Section: Discussioncontrasting

confidence: 48%

Section: Methodssupporting

confidence: 39%

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Increase of telomerase activity and hTERT expression in myelodysplastic syndromes

Briatore¹,

Barrera²,

Pizzimenti³

et al. 2009

Cancer Biology & Therapy

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“…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.…”

Section: Introductionmentioning

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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“…4 Approximately two thirds of patients present with lower-risk disease (Low and Int-1 IPSS scores) characterized by increased rates of apoptosis in the progenitor and differentiated cell compartments in the marrow. [5][6][7][8] High intramedullary apoptosis leads to ineffective hematopoiesis and peripheral cytopenias. Higher grade or more advanced disease categories (Int-2 and High IPSS scores) are associated with a significant risk of leukemia transformation with a corresponding lower apoptotic index and higher percentage of marrow blasts.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors

Navas

Mohindru

Estes

et al. 2006

Blood

118

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The myelodysplastic syndromes (MDSs) are collections of heterogeneous hematologic diseases characterized by refractory cytopenias as a result of ineffective hematopoiesis. Development of effective treatments has been impeded by limited insights into any unifying pathogenic pathways. We provide evidence that the p38 MAP kinase is constitutively activated or phosphorylated in MDS bone marrows. Such activation is uniformly IntroductionThe myelodysplastic syndromes (MDSs) comprise a spectrum of stem-cell malignancies characterized by cytologic dysplasia and ineffective hematopoiesis. [1][2][3] Although approximately one third of patients may experience progression to acute leukemia, refractory cytopenias are the principal cause of morbidity and mortality. MDS can be divided into low-and high-risk subtypes using the International Prognostic Scoring System (IPSS), based on features such as the number of hematopoietic deficits, the percentage of marrow blasts, and cytogenetic pattern. 4 Approximately two thirds of patients present with lower-risk disease (Low and Int-1 IPSS scores) characterized by increased rates of apoptosis in the progenitor and differentiated cell compartments in the marrow. [5][6][7][8] High intramedullary apoptosis leads to ineffective hematopoiesis and peripheral cytopenias. Higher grade or more advanced disease categories (Int-2 and High IPSS scores) 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 contributes in part to ineffective hematopoiesis in MDS. Tumor necrosis factor-␣ (TNF␣) has been implicated in the increased stem-cell apoptosis seen in MDS, 9,10 and high expression of TNF receptors and TNF mRNA have been reported in MDS bone marrows. [11][12][13][14] Transforming growth factor-␤ (TGF␤), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and interferon (IFN-␥ and -␣) are also myelosuppressive, and these proinflammatory cytokines have been found to be elevated in serum of patients with MDS in various studies and are hypothesized to play a role in suppressing hematopoiesis in this disease. 9,11,[15][16][17] Because multiple cytokines are involved in promoting abnormal hematopoietic development in MDS, targeting one single cytokine may not yield appreciable clinical benefit. In fact, anti-TNF therapeutic strategies (monoclonal antibodies and TNFR blockers) have only shown minimal efficacy. [18][19][20][21] Thus, it is imperative to identify common targetable pathways that regulate many different cytokines. Our previous studies have shown that myelosuppressive cytokines such as interferons (IFN-␣, -␤, and -␥), TGF␤, and TNF␣ can all activate the p38 mitogen activated protein kinase (MAPK) in ...

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Imbalance Between Apoptosis and Telomerase Activity in Myelodysplastic Syndromes: Possible Role in Ineffective Hemopoiesis

Cited by 25 publications

References 31 publications

Increase of telomerase activity and hTERT expression in myelodysplastic syndromes

Increase of telomerase activity and hTERT expression in myelodysplastic syndromes

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

Inhibition of overactivated p38 MAPK can restore hematopoiesis in myelodysplastic syndrome progenitors

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