Myelodysplastic syndromes: the complexity of stem-cell diseases

Corey, Seth J.; Minden, Mark D.; Barber, Dwayne L.; Kantarjian, Hagop M.; Wang, Jean; Schimmer, Aaron D.

doi:10.1038/nrc2047

Cited by 319 publications

(306 citation statements)

References 110 publications

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“…MDSs constitute a set of diseases characterized first by excessive and later by the absence of apoptosis involving myeloid cells (Corey et al, 2007). Aberrant PI 3 0 kinase/ Akt activity, which promotes cell survival, may contribute to disease progression from low-risk MDS to high-risk MDS, culminating in AML.…”

Section: Discussionmentioning

confidence: 99%

“…The myelodysplastic syndromes (MDSs) are a heterogeneous group of hematological disorders with poorly understood pathophysiology (Corey et al, 2007). The incidence of MDS is increasing because of more accurate diagnosis, improved classification of myeloid disorders, better supportive care and an aging population (Aul et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

“…Activation of oncogenes or inactivation of tumor suppressor genes has not been well established in MDS, as they have in de novo AML. Complex cytogenetics and a poor therapeutic response to cytarabine are other features that distinguish MDS blasts from those in de novo AML (Corey et al, 2007). Recognizing these differences, we set out to determine why apoptosis is dysregulated as MDS evolves to AML.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…1 Many MDS patients will also progress to acute myeloid leukemia (AML) on acquisition of additional mutations in the defective HSPC compartment. 2 Accurate diagnosis, prognosis and treatment of MDS is hindered because of the heterogeneity and complexity of the disease.…”

Section: Myelodysplastic Syndrome (Mds)mentioning

confidence: 99%

Deregulation of microRNAs in myelodysplastic syndrome

Rhyasen

Starczynowski

2011

Leukemia

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Myelodysplastic syndromes (MDSs) consist of a family of hematopoietic stem cell (HSC) disorders characterized by ineffective differentiation of hematopoietic progenitors, bone marrow dysplasia, genetic instability and a propensity to develop acute myeloid leukemia. The development of MDS is poorly understood and therefore, effective treatment options are limited. Recent progress has been made in identifying altered signaling pathways and understanding the HSC defects, which are thought to contribute to the pathogenesis of MDS. Several of these findings have implicated aberrant expression and function of microRNAs (miRNAs). Unique miRNA expression patterns have been identified in MDS patients and modeled in mice to recapitulate features of MDS. Here, we review miRNA expression profiles identified in MDS patients, and describe the association of miRNA expression with MDS subtypes and disease outcome, clinical implications of miRNAs in MDS and deregulation of miRNAs in mouse model systems of MDS.

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“…MDS may occur de novo or after exposure to mutagens, such as chemotherapy or radiation, manifesting between a few months or years afterward [4,5]. ddMDS is a rare but increasingly recognized complication of HSCT that represents both a diagnostic dilemma and a therapeutic challenge.…”

mentioning

confidence: 99%