Myelodysplastic Syndromes

Greenberg, PL; Attar, Eyal C.; Jm, Bennett; Cd, Bloomfield; Castro, de; Deeg, H. Joachim; Jm, Foran; Gaensler, Karin; Garcia‐Manero, Guillermo; Sd, Gore; Head, David R.; Komrokji, Rami S.; Lj, Maness; Millenson, Michael; Nimer, S.; Mr, O'Donnell; Ma, Schroeder; Pj, Shami; Rm, Stone; Je, Thompson; Westervelt, Peter

doi:10.6004/jnccn.2011.0005

Cited by 175 publications

(84 citation statements)

References 118 publications

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“…As the disease progresses to late-stage MDS, apoptosis is reduced, a block in differentiation develops and blasts accumulate. Approximately 40-50% of those with high-risk disease (Greenberg et al, 2002) will progress to acute myeloid leukemia (AML). Progression of the disease over several years strongly supports a multistep evolution of the malignant MDS stem cell clone (Fenaux, 2004).…”

Section: Introductionmentioning

confidence: 99%

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

et al. 2012

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The myelodysplastic syndromes (MDSs) comprise a group of disorders characterized by multistage progression from cytopenias to acute myeloid leukemia (AML). They display exaggerated apoptosis in early stages, but lose this behavior during evolution to AML. The molecular basis for loss of apoptosis is unknown. To investigate this critical event, we analyzed phosphatidylinositol (PI) 3 0 kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3 0 kinase activates Akt through its production of 3 0 phosphoinositides. In turn, the phosphoinositides are dephosphorylated by two lipid phosphatases, PTEN and SHIP-1, in myeloid cells. We studied primary MDS-enriched bone marrow cells and bone marrow sections by western blotting, immunohistochemistry, immunocytochemistry and quantitative PCR for components of the SHIP/PTEN/PI 3 0 kinase signaling circuit. We reported constitutively activated Akt, variable levels of PTEN and uniformly decreased SHIP-1 expression in MDS progenitor cells. Overexpression of SHIP-1, but not the phosphatase-deficient form, inhibited myeloid leukemic growth. Levels of microRNA (miR)-210 and miR-155 transcripts, which target SHIP-1, were increased in CD34 þ MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3 0 untranslated region of SHIP-1 was confirmed by luciferase reporter assay. Transfection of a myeloid cell line with miR-210 resulted in loss of SHIP-1 protein expression. These data suggest that miR-155 and miR-210/SHIP-1/Akt pathways could serve as clinical biomarkers for disease progression, and that miR-155 and miR-210 might serve as novel therapeutic targets in MDS.

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Section: Introductionmentioning

confidence: 99%

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

et al. 2012

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“…In contrast, in advanced MDS (high-risk MDS), a progressive increase in myeloblasts, coupled with a decrease in apoptosis, and increased genomic instability is observed. 1,2 Karyotypic abnormalities are reported in about 50% of patients with primary MDS and 80% of patients with secondary MDS. 10 The characteristic MDS abnormalities involve loss of genetic material, whereas balanced translocations are rare.…”

Section: Introductionmentioning

confidence: 99%

“…The majority of MDS patients will succumb to the disease over time, because of infection as a result of neutropenia and/or neutrophilic dysfunction or the development of AML. 1,2 With the exceptions of lenalidomide, which is effective in MDS with the del(5q) 17 and hypomethylating agents such as azacitidine, which is used to treat advanced MDS and may improve overall survival by several months, 18 there are few effective drug treatments for this disorder. 19 MDS-associated leukemia does not respond well to chemotherapy and patients have a poor prognosis.…”

Section: Introductionmentioning

confidence: 99%

“…Approximately 40% of MDS patients develop AML. 1,2 MDS is one of the commonest myeloid malignancies and is at least as common as AML. 3,4 The classification of MDS is based on morphologic anomalies according to the French-American-British Cooperative Study Group.…”

Section: Introductionmentioning

confidence: 99%

“…1,2 The MDS are pre-leukemic conditions showing frequent progression to acute myeloid leukemia (AML). Approximately 40% of MDS patients develop AML.…”

Section: Introductionmentioning

confidence: 99%

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Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

et al. 2010

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To gain insight into the molecular pathogenesis of the myelodysplastic syndromes (MDS), we performed global gene expression profiling and pathway analysis on the hematopoietic stem cells (HSC) of 183 MDS patients as compared with the HSC of 17 healthy controls. The most significantly deregulated pathways in MDS include interferon signaling, thrombopoietin signaling and the Wnt pathways. Among the most significantly deregulated gene pathways in early MDS are immunodeficiency, apoptosis and chemokine signaling, whereas advanced MDS is characterized by deregulation of DNA damage response and checkpoint pathways. We have identified distinct gene expression profiles and deregulated gene pathways in patients with del(5q), trisomy 8 or À7/del(7q). Patients with trisomy 8 are characterized by deregulation of pathways involved in the immune response, patients with À7/del(7q) by pathways involved in cell survival, whereas patients with del(5q) show deregulation of integrin signaling and cell cycle regulation pathways. This is the first study to determine deregulated gene pathways and ontology groups in the HSC of a large group of MDS patients. The deregulated pathways identified are likely to be critical to the MDS HSC phenotype and give new insights into the molecular pathogenesis of this disorder, thereby providing new targets for therapeutic intervention.

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Deferasirox for managing iron overload in people with myelodysplastic syndrome

Meerpohl

Schell

Rücker

et al. 2014

Cochrane Database of Systematic Reviews

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We planned to report evidence from RCTs that evaluated the effectiveness of deferasirox compared to either placebo, no treatment or other chelating regimens, such as deferoxamine, in people with MDS. However, we did not identify any completed RCTs addressing this question.We found three ongoing and one completed RCT (published as an abstract only and in insufficient detail) comparing deferasirox with deferoxamine, placebo or no treatment and data will hopefully be available soon. These results will be important to inform physicians and patients on the advantages and disadvantages of this treatment option.

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Myelodysplastic Syndromes

Cited by 175 publications

References 118 publications

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155

Deregulated gene expression pathways in myelodysplastic syndrome hematopoietic stem cells

Deferasirox for managing iron overload in people with myelodysplastic syndrome

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