STAT3β is a tumor suppressor in acute myeloid leukemia
STAT3β is a tumor suppressor in acute myeloid leukemia
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DOI：
10.1182/bloodadvances.2018026385
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发表时间：
2019-07-09
期刊：
影响因子：
7.5
通讯作者：
Stoiber, Dagmar
中科院分区：
文献类型：
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作者：
Aigner, Petra;Mizutani, Tatsuaki;Stoiber, Dagmar
信号转导子和转录激活子3（STAT 3）存在于2种选择性剪接的同种型中，STAT 3 α和STAT 3 β。尽管截短的STAT 3 β最初被假定为STAT 3 α的显性负性形式，但已显示其具有多种STAT 3 α-依赖性调节功能。最近，STAT 3 β作为一种强大的抗肿瘤分子在癌症中受到关注。STAT 3信号转导失调通常见于急性髓性白血病（AML）;然而，STAT 3 β在AML中的作用仍然难以捉摸。因此，我们分析了AML患者的STAT 3 β/α信使RNA（mRNA）表达比率，我们观察到较高的STAT 3 β/α mRNA比率与良好的预后和总生存期增加相关。为了更好地了解STAT 3 β在AML中的功能，我们设计了一种允许平衡Stat 3 β表达的转基因小鼠。在PTEN和MLL-AF 9依赖性AML小鼠模型中，转基因Stat 3 β表达导致疾病进展减缓和生存期延长。我们的研究结果进一步表明，STAT 3 β的抗肿瘤功能取决于通过RNA测序鉴定的一小部分显着上调和下调基因的肿瘤内在调节。总之，我们证明了STAT 3 β在AML中起着重要的肿瘤抑制作用。
Signal transducer and activator of transcription 3 (STAT3) exists in 2 alternatively spliced isoforms, STAT3 alpha and STAT3 beta. Although truncated STAT3 beta was originally postulated to act as a dominant-negative form of STAT3 alpha, it has been shown to have various STAT3 alpha-aindependent regulatory functions. Recently, STAT3 beta gained attention as a powerful antitumorigenic molecule in cancer. Deregulated STAT3 signaling is often found in acute myeloid leukemia (AML); however, the role of STAT3 beta in AML remains elusive. Therefore, we analyzed the STAT3 beta/alpha messenger RNA (mRNA) expression ratio in AML patients, where we observed that a higher STAT3 beta/alpha mRNA ratio correlated with a favorable prognosis and increased overall survival. To gain better understanding of the function of STAT3 beta in AML, we engineered a transgenic mouse allowing for balanced Stat3 beta expression. Transgenic Stat3 beta expression resulted in decelerated disease progression and extended survival in PTEN- and MLL-AF9-dependent AML mouse models. Our findings further suggest that the antitumorigenic function of STAT3 beta depends on the tumor-intrinsic regulation of a small set of significantly up- and downregulated genes, identified via RNA sequencing. In conclusion, we demonstrate that STAT3 beta plays an essential tumor-suppressive role in AML.