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Genome-wide Screen for miRNA Targets Using the MISSION Target ID Library
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Published on: April 6, 2012

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

D W Lee1, M Futami, M Carroll

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

Oncogene
|January 18, 2012
PubMed

Insights

Myelodysplastic syndromes (MDSs) involve a loss of apoptosis during progression to acute myeloid leukemia (AML). This study identifies dysregulated microRNA (miR)-210 and miR-155 targeting SHIP-1 as key drivers of this process.

Area of Science:

  • Hematology
  • Molecular Biology
  • Oncology

Background:

  • Myelodysplastic syndromes (MDSs) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and a high risk of transformation to acute myeloid leukemia (AML).
  • A hallmark of MDS progression to AML is the loss of apoptosis, a programmed cell death mechanism, yet the underlying molecular mechanisms remain largely unknown.
  • Phosphatidylinositol 3'-kinase (PI3K)/Akt signaling is crucial for cell survival and is frequently dysregulated in malignancies, including MDS and AML.

Purpose of the Study:

  • To investigate the molecular basis for the loss of apoptosis during MDS progression to AML.
  • To analyze the role of the SHIP/PTEN/PI 3'-kinase signaling pathway in MDS pathogenesis.
  • To identify potential microRNA (miRNA)-based therapeutic targets in MDS.

Main Methods:

  • Analysis of primary MDS-enriched bone marrow cells and bone marrow sections using western blotting, immunohistochemistry, immunocytochemistry, and quantitative PCR.
  • Assessment of PI 3'-kinase signaling components, including Akt, PTEN, and SHIP-1.
  • Evaluation of microRNA (miR)-210 and miR-155 expression and their direct targeting of SHIP-1 via luciferase reporter assays and cell line transfections.

Main Results:

  • Constitutively activated Akt and uniformly decreased SHIP-1 expression were observed in MDS progenitor cells.
  • Overexpression of SHIP-1 inhibited myeloid leukemic cell growth, while levels of miR-210 and miR-155 transcripts, which target SHIP-1, were increased in MDS cells.
  • miR-210 was confirmed to directly bind to the 3' untranslated region of SHIP-1, leading to reduced SHIP-1 protein expression in myeloid cell lines.

Conclusions:

  • The miR-155 and miR-210/SHIP-1/Akt signaling pathways are dysregulated in MDS and contribute to the loss of apoptosis during disease progression.
  • These pathways represent potential clinical biomarkers for monitoring MDS progression.
  • miR-155 and miR-210 are identified as potential novel therapeutic targets for MDS treatment.

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