title: Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155.
abstract: 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'kinase signaling, implicated as a critical pathway of cell survival control in epithelial and hematological malignancies. PI 3'kinase activates Akt through its production of 3' 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'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(+) MDS cells compared with their normal counterparts. Direct binding of miR-210 to the 3' 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.
authors.affiliation: Division of Pediatrics, University of Texas-MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: D W
authors.initials: DW
authors.lastname: Lee
authors.forename: M
authors.initials: M
authors.lastname: Futami
authors.forename: M
authors.initials: M
authors.lastname: Carroll
authors.forename: Y
authors.initials: Y
authors.lastname: Feng
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: M
authors.initials: M
authors.lastname: Fernandez
authors.forename: Z
authors.initials: Z
authors.lastname: Whichard
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Kornblau
authors.forename: E J
authors.initials: EJ
authors.lastname: Shpall
authors.forename: C E
authors.initials: CE
authors.lastname: Bueso-Ramos
authors.forename: S J
authors.initials: SJ
authors.lastname: Corey
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001854:Bone Marrow Cells / Q000378:metabolism; D045744:Cell Line, Tumor; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D009190:Myelodysplastic Syndromes / Q000235:genetics / Q000378:metabolism*; D022423:Myeloid Cells / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction
chemical_list: C524942:MIRN155 microRNA, human; C543800:MIRN210 microRNA, human; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C000606430:INPP5D protein, human; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases