miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia.
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.
Klusmann
Jan-Henning
JH
Children's Hospital Boston, Massachusetts 02115, USA.
Li
Zhe
Z
Böhmer
Katarina
K
Maroz
Aliaksandra
A
Koch
Mia Lee
ML
Emmrich
Stephan
S
Godinho
Frank J
FJ
Orkin
Stuart H
SH
Reinhardt
Dirk
D
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D019295:Computational Biology; D053487:DEAD-box RNA Helicases / Q000235:genetics; D004314:Down Syndrome / Q000150:complications; D050982:GATA1 Transcription Factor / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic; D055785:Gene Knockdown Techniques; D006801:Humans; D020014:K562 Cells; D007947:Leukemia, Megakaryoblastic, Acute / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D055016:Megakaryocyte Progenitor Cells / Q000166:cytology / Q000378:metabolism; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D034622:RNA Interference; D012097:Repressor Proteins / Q000235:genetics; D043244:Ribonuclease III / Q000235:genetics
D050982:GATA1 Transcription Factor; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; D012097:Repressor Proteins; C497230:ST18 protein, human; C408087:DICER1 protein, human; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases