Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways.
Dysfunction of the WT1-MEG3 signaling promotes AML leukemogenesis via p53-dependent and -independent pathways.
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WT1-MEG3 信号传导功能障碍通过 p53 依赖性和非依赖性途径促进 AML 白血病发生
作者：
Lyu Y;Lou J;Yang Y;Feng J;Hao Y;Huang S;Yin L;Xu J;Huang D;Ma B;Zou D;Wang Y;Zhang Y;Zhang B;Chen P;Yu K;Lam EW;Wang X;Liu Q;Yan J;Jin B
长链非编码rna （lncRNAs）在肿瘤发生中起着关键作用，最近发现lncRNA母源表达基因3 （MEG3）以p53依赖的方式抑制肿瘤生长。急性髓系白血病（AML）是成人中最常见的恶性髓系疾病，TP53突变或缺失常见于治疗相关性AML或复杂核型AML患者。在这里，我们发现MEG3在AML中显著下调，并且不仅以p53依赖的方式抑制白血病发生，而且以p53不依赖的方式抑制白血病发生。此外，MEG3被证实可被Wilms ' tumor 1 （WT1）转录激活，而WT1通过表观遗传沉默或突变导致的失调与AML有因果关系。因此，MEG3被确定为WT1分子的新靶点。10 - 11易位-2 （TET2）突变经常发生在AML中，并显著促进这种疾病的白血病发生。在我们的研究中，TET2作为WT1的辅助因子，增加了MEG3的表达。综上所述，我们的工作表明TET2失调的WT1-MEG3轴显著促进AML白血病的发生，为AML患者的诊断和治疗开辟了新的途径。
Long non-coding RNAs (lncRNAs) play a pivotal role in tumorigenesis, exemplified by the recent finding that lncRNA maternally expressed gene 3 (MEG3) inhibits tumor growth in a p53-dependent manner. Acute myeloid leukemia (AML) is the most common malignant myeloid disorder in adults, and TP53 mutations or loss are frequently detected in patients with therapy-related AML or AML with complex karyotype. Here, we reveal that MEG3 is significantly downregulated in AML and suppresses leukemogenesis not only in a p53-dependent, but also a p53-independent manner. In addition, MEG3 is proven to be transcriptionally activated by Wilms’ tumor 1 (WT1), dysregulation of which by epigenetic silencing or mutations is causally involved in AML. Therefore MEG3 is identified as a novel target of the WT1 molecule. Ten–eleven translocation-2 (TET2) mutations frequently occur in AML and significantly promote leukemogenesis of this disorder. In our study, TET2, acting as a cofactor of WT1, increases MEG3 expression. Taken together, our work demonstrates that TET2 dysregulated WT1-MEG3 axis significantly promotes AML leukemogenesis, paving a new avenue for diagnosis and treatment of AML patients.
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长链非编码RNA MEG3通过影响p53表达抑制NSCLC细胞增殖并诱导细胞凋亡。
影响因子：
3.8
作者：
Lu KH;Li W;Liu XH;Sun M;Zhang ML;Wu WQ;Xie WP;Hou YY
通讯作者：
Hou YY
影响因子：
64.5
作者：
CALL, KM;GLASER, T;HOUSMAN, DE
通讯作者：
HOUSMAN, DE
TET2相互作用者及其与血液学恶性肿瘤的联系。
影响因子：
4.6
作者：
Pan F;Weeks O;Yang FC;Xu M
通讯作者：
Xu M
影响因子：
6.4
作者：
Jia, Ling-Fei;Wei, Su-Bi;Yu, Guang-Yan
通讯作者：
Yu, Guang-Yan
影响因子：
158.5
作者：
Delhommeau, Francois;Dupont, Sabrina;Bernard, Olivier A.
通讯作者：
Bernard, Olivier A.