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

Oncogene volume 31, pages 4085–4094 (2012)Cite this article

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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.

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Acknowledgements

We thank Martin H Nguyen for technical assistance. We thank Drs Gerald Krystal for providing the cDNA for SHIP-1 and Maria-Magdalena Georgescu for control lysates. SJC was funded by the NIH Independent Scientist Award KO2-HL03794, RO1-CA108992, American Cancer Society Research Scholar Grant DHP-135, Ladies Leukemia League, JP McCarthy Foundation, NIH PO1CA55164 and Leukemia SPORE CA100632. Funding also came from the AA/MDS International Foundation to both SJC and MF.

Author contributions: MC, CEB-R, DWL and SJC designed the research. DWL, YF, ZW, MF, ZW and SAJ performed the research.SK and EJS contributed the reagents.DWL, MF, MC, CEB-R, ZW and SJC analyzed the data. DWL, MF, ZW and SJC wrote the paper.

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  1. D W Lee and M Futami: These are co-first authors.

Authors and Affiliations

  1. Division of Pediatrics, University of Texas—MD Anderson Cancer Center, Houston, TX, USA

    D W Lee

  2. Division of Pediatrics and the Robert H Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA

    M Futami, Y Feng, Z Wang, Z Whichard, Y Chen & S J Corey

  3. Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA, USA

    M Carroll

  4. Department of Hematopathology, University of Texas—MD Anderson Cancer Center, Houston, TX, USA

    M Fernandez & C E Bueso-Ramos

  5. Department of Leukemia, University of Texas—MD Anderson Cancer Center, Houston, TX, USA

    S Kornblau

  6. Department of Blood and Marrow Transplantation, University of Texas—MD Anderson Cancer Center, Houston, TX, USA

    E J Shpall

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Lee, D., Futami, M., Carroll, M. et al. Loss of SHIP-1 protein expression in high-risk myelodysplastic syndromes is associated with miR-210 and miR-155. Oncogene 31, 4085–4094 (2012). https://doi.org/10.1038/onc.2011.579

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