miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia
miR-125b-2 is a potential oncomiR on human chromosome 21 in megakaryoblastic leukemia
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DOI：
10.1101/gad.1856210
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发表时间：
2010-03-01
影响因子：
10.5
通讯作者：
Reinhardt, Dirk
中科院分区：
文献类型：
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作者：
Klusmann, Jan-Henning;Li, Zhe;Reinhardt, Dirk
21三体/唐氏综合征(DS)儿童是发生急性巨核细胞白血病(DS-AMKL)和相关一过性白血病(DS-TL)的高危人群。人类21号染色体(Hsa21)上导致这种易感效应的因素，特别是与持续突变的转录因子GATA1(GATA1)协同作用的因素，目前仍知之甚少。在这里，我们研究了Hsa21编码的miR-125b-2，一种在DS-AMKL/TL中过表达的微RNA(MiRNA)，在造血和白血病发生中的作用。我们鉴定了miR-125b-2在促进人和小鼠巨核系祖细胞(MPS)和巨核/红系祖细胞(MEP)增殖和自我更新中的作用。MiR-125b-2过表达不影响巨核细胞和红系分化，但严重干扰髓系分化。MiR-125b-2对MEPs的促增殖作用加剧了Gata1S突变，而抑制miR-125b则抑制了DS-AMKL/TL细胞的生长，提示GATA1突变的DS-AMKL/TL在白血病转化过程中具有协同作用。对调节miR-125b表达水平的造血细胞进行整合转录组分析，发现了一组miR-125b靶基因，包括作为直接靶点的DICER1和ST18。基因集浓缩分析显示，该靶基因集在高表达miR-125b的DS-AMKL患者中下调。因此，我们认为miR-125b-2是巨核细胞生成的正调控因子，也是参与21三体相关巨核细胞白血病发病机制的肿瘤因子。
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.