Published online 10 March 2009
Haematologica, Vol 94, Issue 4, 479-486 doi:10.3324/haematol.2008.002345
Copyright © 2009 by Ferrata Storti Foundation

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Erythropoiesis

MicroRNA 223-dependent expression of LMO2 regulates normal erythropoiesis

Nadia Felli¹, Francesca Pedini¹, Paolo Romania¹, Mauro Biffoni¹, Ornella Morsilli¹, Germana Castelli¹, Simona Santoro¹, Simona Chicarella¹, Antonio Sorrentino¹, Cesare Peschle^1,2, Giovanna Marziali¹

¹ Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome
² IRCCS MultiMedica, Milan, Italy

Correspondence: Nadia Felli, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail:nadia.felli{at}iss.it, Giovanna Marziali, Dept. of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail:giovanna.marziali{at}iss.it

Background: MicroRNAs are small non-coding RNAs that regulate gene expression through mRNA degradation or translational inhibition. MicroRNAs are emerging as key regulators of normal hematopoiesis and hematologic malignancies. Several miRNAs are differentially expressed during hematopoiesis and their specific expression regulates key functional proteins involved in hematopoietic lineage differentiation. This study focused on the functional role of microRNA-223 (miR-223) on erythroid differentiation.

Design and Methods: Purified cord blood CD34⁺ hematopoietic progenitor cells were grown in strictly controlled conditions in the presence of saturating dosage of erythropoietin to selectively induce erythroid differentiation. The effects of enforced expression of miR-223 in unilin-eage erythroid cultures were evaluated in liquid phase culture experiments and clonogenic studies.

Results: In unilineage erythroid culture of cord blood CD34⁺ hematopoietic progenitor cells miR-223 is down-regulated, whereas LMO2, an essential protein for erythroid differentiation, is up-regulated. Functional studies showed that enforced expression of miR-223 reduces the mRNA and protein levels of LMO2, by binding to LMO2 3’ UTR, and impairs differentiation of erythroid cells. Accordingly, knockdown of LMO2 by short interfering RNA mimics the action of miR-223. Furthermore, hematopoietic progenitor cells transduced with miR-223 showed a significant reduction of their erythroid clonogenic capacity, suggesting that downmodulation of this miRNA is required for erythroid progenitor recruitment and commitment.

Conclusions: These results show that the decline of miR-223 is an important event for erythroid differentiation that leads to the expansion of erythroblast cells at least partially mediated by unblocking LMO2 protein expression.

Key words: hematopoietic progenitors cells, erythroid differentiation, microRNA, transcription factors.

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