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J Thromb Haemost. 2015 Nov;13(11):2108-18. doi: 10.1111/jth.13150. Epub 2015 Oct 23.

Eukaryotic translation initiation factor 6 is a novel regulator of reactive oxygen species-dependent megakaryocyte maturation.

Author information

1
Molecular Histology and Cell Growth Unit, National Institute of Molecular Genetics - INGM, 'Romeo ed Enrica Invernizzi', Milan, Italy.
2
Centre for Computational Biology and Modeling, Institute of Integrative Biology, University of Liverpool, Liverpool, UK.
3
Immunopathology Unit, San Raffaele Scientific Institute, Milan, Italy.

Abstract

BACKGROUND:

Ribosomopathies constitute a class of inherited disorders characterized by defects in ribosome biogenesis and function. Classically, bone marrow (BM) failure is a clinical symptom shared between these syndromes, including Shwachman-Bodian-Diamond syndrome (SBDS). Eukaryotic translation initiation factor 6 (eIF6) is a critical translation factor that rescues the quasilethal effect of the loss of the SBDS protein.

OBJECTIVES:

To determine whether eIF6 activity is necessary for BM development.

METHODS:

We used eIF6(+/-) mice and primary BM megakaryocytes to investigate the involvement of eIF6 in the regulation of hematopoiesis.

RESULTS:

We provide evidence that reduced eIF6 expression negatively impacts on megakaryopoiesis. We show that inhibition of eIF6 leads to a reduction in cell size and mean ploidy level of megakaryocytes and a delay in megakaryocyte maturation by blocking the G1 /S transition. Consistent with this phenotype, only few megakaryocyte-forming proplatelets were found in eIF6(+/-) cells. We also discovered that, in eIF6(+/-) cells, the steady-state abundance of mitochondrial respiratory chain complex I-encoding mRNAs is decreased, resulting in decreased reactive oxygen species (ROS) production. Intriguingly, connectivity map analysis showed that eIF6-mediated changes overlap with specific translational inhibitors. eIF6 is a translation factor acting downstream of insulin/phorbol 12-myristate 13-acetate (PMA) stimulation. PMA treatment significantly restored eIF6(+/-) megakaryocyte maturation, indicating that activation of eIF6 is essential for the rescue of the phenotype.

CONCLUSIONS:

Taken together, our results show a role for eIF6-driven translation in megakaryocyte development, and unveil the novel connection between translational control and ROS production in this cell subset.

KEYWORDS:

initiation factors; megakaryocytes; platelets; reactive oxygen species; thrombocytopenia

PMID:
26391622
DOI:
10.1111/jth.13150
[Indexed for MEDLINE]
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