miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia.
miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia.
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DOI：
10.1038/ncomms1681
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发表时间：
2012-02-21
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
--
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HOXA9 和 MEIS1 在混合谱系白血病 (MLL) 重排白血病中具有重要的致癌作用。在这里，我们证明它们是 miRNA-196b 的直接靶标，miRNA-196b 是 MLL 重排白血病细胞中与 HOXA9 相邻并共表达的一种 microRNA (miRNA)。 miR-196b 的强制表达通过抑制 Hoxa9/Meis1 表达，显着延迟原代骨髓移植中 MLL 融合介导的白血病发生。然而，与单独的 MLL 融合相比，miR-196b 的异位表达会导致更具侵袭性的白血病表型，并在二次移植中导致更快的白血病发生，这可能是通过进一步抑制 Fas 表达（MLL 重排白血病中下调的促凋亡基因）实现的。 FAS 的过表达可显着抑制白血病发生并逆转 miR-196b 介导的表型。 miR-196b 靶向 Hoxa9/Meis1 和 Fas 可能对正常造血也很重要。因此，我们的结果揭示了一种以前未被认识到的 miRNA 调节机制，通过该机制，单个 miRNA 可以在每个细胞分化的肿瘤发生和正常发育中同时或依次靶向癌基因和肿瘤抑制基因，这表明 miRNA 调节比以前想象的要复杂得多。 HOX9A 和 MEIS1 是 MLL 重排白血病的关键癌基因。这里显示 miRNA-196b 可以直接抑制它们的表达并延迟 MLL 融合介导的白血病，但当异位表达时也会引起侵袭性白血病表型，这表明它也以肿瘤抑制因子为目标。
HOXA9 and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought. HOX9A and MEIS1 are key oncogenes in MLL-rearranged leukaemia. miRNA-196b is shown here to directly suppress their expression and delay MLL-fusion-mediated leukaemia, but to also cause an aggressive leukaemia phenotype when expressed ectopically, suggesting that it targets tumour suppressors as well.
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