miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia
- Jan-Henning Klusmann1,2,7,
- Zhe Li1,3,4,7,
- Katarina Böhmer2,
- Aliaksandra Maroz2,
- Mia Lee Koch2,
- Stephan Emmrich2,
- Frank J. Godinho1,5,
- Stuart H. Orkin1,3,5,6,8 and
- Dirk Reinhardt2
- 1Division of Hematology/Oncology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;
- 2Department of Pediatric Hematology/Oncology, Medical School Hannover, Hannover 30625, Germany;
- 3Harvard Medical School and Harvard Stem Cell Institute, Boston, Massachusetts 02115, USA;
- 4Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA;
- 5Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
- 6Howard Hughes Medical Institute, Boston, Massachusetts 02115, USA
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↵7 These authors contributed equally to this work.
Abstract
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 GATA1 (GATA1s), remain poorly understood. Here, we investigated the role of Hsa21-encoded miR-125b-2, a microRNA (miRNA) overexpressed in DS-AMKL/TL, in hematopoiesis and leukemogenesis. We identified a function of miR-125b-2 in increasing proliferation and self-renewal of human and mouse megakaryocytic progenitors (MPs) and megakaryocytic/erythroid progenitors (MEPs). miR-125b-2 overexpression did not affect megakaryocytic and erythroid differentiation, but severely perturbed myeloid differentiation. The proproliferative effect of miR-125b-2 on MEPs accentuated the Gata1s mutation, whereas growth of DS-AMKL/TL cells was impaired upon miR-125b repression, suggesting synergism during leukemic transformation in GATA1s-mutated DS-AMKL/TL. Integrative transcriptome analysis of hematopoietic cells upon modulation of miR-125b expression levels uncovered a set of miR-125b target genes, including DICER1 and ST18 as direct targets. Gene Set Enrichment Analysis revealed that this target gene set is down-regulated in DS-AMKL patients highly expressing miR-125b. Thus, we propose miR-125b-2 as a positive regulator of megakaryopoiesis and an oncomiR involved in the pathogenesis of trisomy 21-associated megakaryoblastic leukemia.
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Footnotes
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↵8 Corresponding author.
E-MAIL Stuart_Orkin{at}dfci.harvard.edu; FAX (617) 632-4367.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1856210.
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Supplemental material is available at http://www.genesdev.org.
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- Received August 21, 2009.
- Accepted December 23, 2009.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press