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首页> 美国卫生研究院文献>Epigenetics >Frequent epigenetic inactivation of KIBRA an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network is associated with specific genetic event in B-cell acute lymphocytic leukemia
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Frequent epigenetic inactivation of KIBRA an upstream member of the Salvador/Warts/Hippo (SWH) tumor suppressor network is associated with specific genetic event in B-cell acute lymphocytic leukemia

机译：萨尔瓦多/沃尔特/河马（SWH）肿瘤抑制网络上游成员KIBRA的频繁表观遗传失活与B细胞急性淋巴细胞白血病的特定遗传事件有关

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The WW-domain containing protein KIBRA has recently been identified as a new member of the Salvador/Warts/Hippo (SWH) pathway in Drosophila and is shown to act as a tumor suppressor gene in Drosophila. This pathway is conserved in humans and members of the pathway have been shown to act as tumor suppressor genes in mammalian systems. We determined the methylation status of the 5′ CpG island associated with the KIBRA gene in human cancers. In a large panel of cancer cell lines representing common epithelial cancers KIBRA was unmethylated. But in pediatric acute lymphocytic leukemia (ALL) cell lines KIBRA showed frequent hypermethylation and silencing of gene expression, which could be reversed by treatment with 5-aza-2′-deoxycytidine. In ALL patient samples KIBRA was methylated in 70% B-ALL but was methylated in <20% T-ALL leukemia (p = 0.0019). In B-ALL KIBRA methylation was associated with ETV6/RUNX1 [t(12;21) (p13;q22)] chromosomal translocation (p = 0.0082) phenotype, suggesting that KIBRA may play an important role in t(12;21) leukemogenesis. In ALL paired samples at diagnosis and remission KIBRA methylation was seen in diagnostic but not in any of the remission samples accompanied by loss of KIBRA expression in disease state compared to patients in remission. Hence KIBRA methylation occurs frequently in B-cell acute lymphocytic leukemia but not in epithelial cancers and is linked to specific genetic event in B-ALL.
机译：含有WW结构域的蛋白KIBRA最近被确定为果蝇中萨尔瓦多/沃尔特/河马（SWH）途径的新成员，并被证明是果蝇中的抑癌基因。该途径在人类中是保守的，并且已经表明该途径的成员在哺乳动物系统中充当肿瘤抑制基因。我们确定了人类癌症中与KIBRA基因相关的5'CpG岛的甲基化状态。在代表普通上皮癌的一大批癌细胞系中，KIBRA未甲基化。但是在小儿急性淋巴细胞白血病（ALL）细胞系中，KIBRA表现出频繁的甲基化过度和基因表达沉默，这可以通过用5-氮杂2'-脱氧胞苷处理来逆转。在所有患者样品中，KIBRA在70％的B-ALL白血病中被甲基化，但在<20％的T-ALL白血病中被甲基化（p = 0.0019）。在B-ALL中，KIBRA甲基化与ETV6 / RUNX1 [t（12; 21）（p13; q22）]染色体易位（p = 0.0082）表型相关，表明KIBRA可能在t（12; 21）白血病发生中起重要作用。与缓解期患者相比，在诊断和缓解期的所有配对样本中，在诊断中均观察到KIBRA甲基化，但在任何缓解期样本中均未发现KIBRA甲基化，并伴有疾病状态下KIBRA表达的丧失。因此，KIBRA甲基化经常发生在B细胞急性淋巴细胞性白血病中，而不发生在上皮癌中，并且与B-ALL中的特定遗传事件有关。

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