Children's Hospital Boston, Massachusetts 02115, USA.
Genes Dev. 2010 Mar 1;24(5):478-90. doi: 10.1101/gad.1856210.
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.
唐氏综合征（Down syndrome，DS）患儿罹患急性巨核细胞白血病（DS-AMKL）和相关短暂性白血病（DS-TL）的风险较高。目前，导致这种易感性的人类 21 号染色体（Hsa21）上的因素（特别是与持续突变的转录因子 GATA1 [GATA1s] 协同作用的因素）仍知之甚少。在这里，我们研究了 Hsa21 编码的 microRNA（miRNA）miR-125b-2 的作用，该 miRNA 在 DS-AMKL/TL 中过度表达，在造血和白血病发生中发挥作用。我们发现 miR-125b-2 可增加人类和小鼠巨核细胞祖细胞（MPs）和巨核细胞/红细胞祖细胞（MEPs）的增殖和自我更新能力。miR-125b-2 的过表达不会影响巨核细胞和红细胞的分化，但严重干扰了髓系分化。miR-125b-2 对 MEPs 的促增殖作用加重了 Gata1s 突变，而抑制 miR-125b-2 则会损害 DS-AMKL/TL 细胞的生长，这表明在 GATA1s 突变的 DS-AMKL/TL 白血病转化过程中存在协同作用。对 miR-125b 表达水平进行调节后对造血细胞进行的综合转录组分析发现了一组 miR-125b 靶基因，包括 DICER1 和 ST18 作为直接靶基因。基因集富集分析显示，该靶基因集在高表达 miR-125b 的 DS-AMKL 患者中下调。因此，我们提出 miR-125b-2 作为巨核细胞生成的正调节剂和涉及 21 三体相关巨核细胞白血病发病机制的癌基因 miRNA。
