AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia
AML1-ETO requires enhanced C/D box snoRNA/RNP formation to induce self-renewal and leukaemia
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DOI：
10.1038/ncb3563
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发表时间：
2017-07-01
影响因子：
21.3
通讯作者：
Mueller-Tidow, Carsten
中科院分区：
文献类型：
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作者：
Zhou, Fengbiao;Liu, Yi;Mueller-Tidow, Carsten
白血病发生需要增强的自我更新，这是由癌基因诱导的。潜在的分子机制仍然不完全清楚。在这里，我们确定了C/D盒snoRNA和rRNA 2 '-O-甲基化作为白血病干细胞活性的关键决定因素。AML 1-ETO致白血病需要Groucho相关的氨基末端分裂增强子（AES）的表达。AES通过与RNA解旋酶DDX 21相互作用诱导snoRNA/RNP形成而发挥作用。类似地，C/D盒snoRNA的整体丢失伴随着rRNA 2 '-O-甲基化的丢失导致白血病自我更新潜力降低。C/D盒snoRNA SNORD 14 D或SNORD 35 A基因组缺失抑制白血病细胞体外克隆形成潜力，并延迟体内白血病发生。我们进一步表明，AML 1-ETO 9a、MYC和MLL-AF 9都增强snoRNA的形成。AML患者中C/D盒snoRNA的表达水平与白血病干细胞的体内频率密切相关。总的来说，这些发现表明，诱导C/D盒snoRNA/RNP功能构成了白血病发生的重要途径。
Leukaemogenesis requires enhanced self-renewal, which is induced by oncogenes. The underlying molecular mechanisms remain incompletely understood. Here, we identified C/D box snoRNAs and rRNA 2'-O-methylation as critical determinants of leukaemic stem cell activity. Leukaemogenesis by AML1-ETO required expression of the groucho-related amino-terminal enhancer of split (AES). AES functioned by inducing snoRNA/RNP formation via interaction with the RNA helicase DDX21. Similarly, global loss of C/D box snoRNAs with concomitant loss of rRNA 2'-O-methylation resulted in decreased leukaemia self-renewal potential. Genomic deletion of either C/D box snoRNA SNORD14D or SNORD35A suppressed clonogenic potential of leukaemia cells in vitro and delayed leukaemogenesis in vivo. We further showed that AML1-ETO9a, MYC and MLL-AF9 all enhanced snoRNA formation. Expression levels of C/D box snoRNAs in AML patients correlated closely with in vivo frequency of leukaemic stem cells. Collectively, these findings indicate that induction of C/D box snoRNA/RNP function constitutes an important pathway in leukaemogenesis.