Cooperation between RUNX1-ETO9a and novel transcriptional partner KLF6 in upregulation of Alox5 in acute myeloid leukemia.
Cooperation between RUNX1-ETO9a and novel transcriptional partner KLF6 in upregulation of Alox5 in acute myeloid leukemia.
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DOI：
10.1371/journal.pgen.1003765
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发表时间：
2013
期刊：
影响因子：
4.5
通讯作者：
Zhang DE
中科院分区：
文献类型：
--
作者：
DeKelver RC;Lewin B;Lam K;Komeno Y;Yan M;Rundle C;Lo MC;Zhang DE
融合蛋白RUNX1-ETO （AML1-ETO, RUNX1-RUNX1T1）作为8q22的结果表达；21q22易位[t(8;21)]，是急性髓性白血病中最常见的染色体异常之一。RUNX1- eto被认为通过RUNX1 （AML1）靶基因的异常调控促进白血病的发展。这些基因的抑制是通过N-COR和SMRT的募集而发生的，因为它们与ETO相互作用。RUNX1-ETO靶基因上调的机制尚不清楚。我们发现RUNX1-ETO9a是t（8;21）表达的致白血病选择性剪接转录物，上调靶基因Alox5，而Alox5是BCR-ABL促进慢性髓性白血病发展的关键基因。Alox5表达缺失可降低体外RUNX1-ETO9a、MLL-AF9和PML-RARα的活性。然而，在体内，Alox5并不是RUNX1-ETO9a诱导白血病所必需的。最后，我们证明RUNX1-ETO9a通过C2H2锌指转录因子KLF6上调Alox5，这是一种早期造血和卵黄囊发育所需的蛋白质。此外，在人白血病细胞中，RUNX1-ETO特异性上调KLF6。这表明KLF6是t（8;21）靶基因调控的新介质，为RUNX1-ETO转录调控提供了新的机制。8;易位是急性髓性白血病（AML）中最常见的遗传异常之一。这种易位导致融合基因RUNX1-ETO及其剪接异构体的表达。然后，RUNX1-ETO蛋白重新编程细胞的转录景观，并与进一步的突变合作，诱导白血病的发展。在这项研究中，我们研究了RUNX1-ETO靶基因Alox5的转录控制。虽然在小鼠模型中，Alox5对于AML的发展似乎是不可缺少的，但它对于一些RUNX1-ETO功能是必需的。在对Alox5表达调控的研究中，我们发现了一个新的RUNX1-ETO伴侣蛋白KLF6，该蛋白既被RUNX1-ETO上调，又参与RUNX1-ETO基因调控。这为RUNX1-ETO靶基因上调的机制提供了新的见解，并确定了KLF6在t(8;21) AML发展中可能是一个重要的蛋白，可以进一步研究。
Fusion protein RUNX1-ETO (AML1-ETO, RUNX1-RUNX1T1) is expressed as the result of the 8q22;21q22 translocation [t(8;21)], which is one of the most common chromosomal abnormalities found in acute myeloid leukemia. RUNX1-ETO is thought to promote leukemia development through the aberrant regulation of RUNX1 (AML1) target genes. Repression of these genes occurs via the recruitment of the corepressors N-COR and SMRT due to their interaction with ETO. Mechanisms of RUNX1-ETO target gene upregulation remain less well understood. Here we show that RUNX1-ETO9a, the leukemogenic alternatively spliced transcript expressed from t(8;21), upregulates target gene Alox5, which is a gene critically required for the promotion of chronic myeloid leukemia development by BCR-ABL. Loss of Alox5 expression reduces activity of RUNX1-ETO9a, MLL-AF9 and PML-RARα in vitro. However, Alox5 is not essential for the induction of leukemia by RUNX1-ETO9a in vivo. Finally, we demonstrate that the upregulation of Alox5 by RUNX1-ETO9a occurs via the C2H2 zinc finger transcription factor KLF6, a protein required for early hematopoiesis and yolk sac development. Furthermore, KLF6 is specifically upregulated by RUNX1-ETO in human leukemia cells. This identifies KLF6 as a novel mediator of t(8;21) target gene regulation, providing a new mechanism for RUNX1-ETO transcriptional control. The 8;21 translocation is one of the most common genetic abnormalities present in acute myeloid leukemia (AML). This translocation causes expression of the fusion gene RUNX1-ETO and its splicing isoforms. RUNX1-ETO proteins then reprogram the transcriptional landscape of the cell and cooperate with further mutations to induce leukemia development. In this study, we examine the transcriptional control of the RUNX1-ETO target gene Alox5. Although Alox5 appears to be dispensable for AML development in a mouse model, it is required for some RUNX1-ETO functions. In studying the regulation of Alox5 expression, we have discovered a novel RUNX1-ETO partner protein, KLF6, which is both upregulated by RUNX1-ETO and participates in RUNX1-ETO gene regulation. This provides new insight into the under-studied mechanisms of RUNX1-ETO target gene upregulation and identifies KLF6 as a potentially important protein for further study in t(8;21) AML development.
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