You can manage bookmarks using lists, please log in to your user account for this.
Media type:
E-Article
Title:
miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia
Contributor:
Klusmann, Jan-Henning;
Li, Zhe;
Böhmer, Katarina;
Maroz, Aliaksandra;
Koch, Mia Lee;
Emmrich, Stephan;
Godinho, Frank J.;
Orkin, Stuart H.;
Reinhardt, Dirk
imprint:
Cold Spring Harbor Laboratory, 2010
Published in:Genes & Development
Language:
English
DOI:
10.1101/gad.1856210
ISSN:
0890-9369;
1549-5477
Origination:
Footnote:
Description:
<jats:p>Children with trisomy 21/Down syndrome (DS) are at high risk to develop acute megakaryoblastic leukemia (DS-AMKL) and the related transient leukemia (DS-TL). The factors on human chromosome 21 (Hsa21) that confer this predisposing effect, especially in synergy with consistently mutated transcription factor <jats:italic>GATA1</jats:italic> (<jats:italic>GATA1s</jats:italic>), remain poorly understood. Here, we investigated the role of Hsa21-encoded <jats:italic>miR-125b-2</jats:italic>, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of <jats:italic>miR-125b-2</jats:italic> in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). <jats:italic>miR-125b-2</jats:italic> overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of <jats:italic>miR-125b-2</jats:italic> on MEPs accentuated the <jats:italic>Gata1s</jats:italic> mutation, whereas growth of DS-AMKL/TL cells was impaired upon <jats:italic>miR-125b</jats:italic> repression, suggesting synergism during leukemic transformation in <jats:italic>GATA1s</jats:italic>-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of <jats:italic>miR-125b</jats:italic> expression levels uncovered a set of <jats:italic>miR-125b</jats:italic> target genes, including <jats:italic>DICER1</jats:italic> and <jats:italic>ST18</jats:italic> as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing <jats:italic>miR-125b</jats:italic>. Thus, we propose <jats:italic>miR-125b-2</jats:italic> as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.</jats:p>