Destabilization of AETFC through C/EBP alpha-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation
Destabilization of AETFC through C/EBP alpha-mediated repression of LYL1 contributes to t(8;21) leukemic cell differentiation
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C/EBP α 介导的 LYL1 抑制导致 AETFC 不稳定，导致 t(8;21) 白血病细胞分化
DOI：
10.1038/s41375-019-0398-8
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发表时间：
2019
期刊：
影响因子：
11.4
通讯作者：
Sun Xiao Jian
中科院分区：
文献类型：
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作者：
Zhang Meng Meng;Liu Na;Zhang Yuan Liang;Rong Bowen;Wang Xiao Lin;Xu Chun Hui;Xie Yin Yin;Shen Shuhong;Zhu Jiang;Nimer Stephen D;Chen Zhu;Chen Sai Juan;Roeder Robert G;Lan Fei;Lan Wang;Huang Qiu Hua;Sun Xiao Jian
AML 1-ETO融合蛋白由t（8; 21）易位产生，t（8; 21）易位是急性髓细胞白血病（AML）中最常见的染色体异常。虽然AML 1-ETO单独不足以引起白血病，但它是维持白血病所必需的，因此代表了治疗靶点。这一观点得到了多方面证据的支持：（i）小干扰RNA（siRNA）对AML 1-ETO的瞬时抑制增加了白血病细胞对分化的易感性，并延迟了体内白血病发生[1，2];（ii）在携带完全发展的白血病的小鼠模型中，关闭AML 1-ETO导致白血病消退[3];（iii）在AML 1-ETO 9a（AE 9a）驱动的白血病小鼠模型中，帕比司他引发的白血病细胞的髓样分化（HDAC抑制剂）归因于AE 9a降解[4];和（iv）机制研究表明，白血病细胞中AML 1-ETO的耗竭导致全基因组表观遗传重编程和转录因子结合的变化，导致骨髓分化和白血病维持的丧失[5]。我们之前发现，在白血病细胞中，AML 1-ETO通过含AML 1-ETO的转录因子复合物（AETFC）稳定并发挥作用，AETFC含有多种转录（辅）因子，包括AML 1-ETO、CBFβ、E蛋白HEB和E2 A、造血bHLH转录因子LYL 1、LIM结构域蛋白LMO 2及其结合伴侣LDB 1 [6]。这些AETFC组分相互稳定并协同结合和调节靶基因，并且AETFC完整性和正确构象对于白血病发生至关重要[6]。因此，AETFC的不稳定性提供了靶向AML 1-ETO的策略。值得注意的是，已经普遍提出蛋白质复合物的稳定性可以
The AML1-ETO fusion protein is produced by the t (8; 21) translocation, which is the most common chromosomal abnormality in acute myeloid leukemia (AML). Although AML1-ETO alone is insufficient to cause leukemia, it is necessary for maintaining leukemia and therefore represents a therapeutic target. This notion has been supported by several lines of evidence:(i) transient suppression of AML1-ETO by small interfering RNA (siRNA) increases susceptibility of the leukemic cells to differentiation and delays leukemogenesis in vivo [1, 2];(ii) in a mouse model harboring fully developed leukemia, switching off AML1-ETO leads to leukemia regression [3];(iii) in an AML1-ETO9a (AE9a)-driven leukemic mouse model, myeloid differentiation of leukemic cells triggered by panobinostat (an HDAC inhibitor) was attributed to AE9a degradation [4]; and (iv) mechanistic studies revealed that depletion of AML1-ETO in leukemic cells leads to a genome-wide epigenetic reprogramming and changes in transcription factor binding, resulting in myeloid differentiation and loss of leukemia maintenance [5]. We previously found that, in leukemic cells, AML1-ETO is stabilized and functions through the AML1-ETO-containing transcription factor complex (AETFC), which contains multiple transcription (co) factors that include AML1-ETO, CBFβ, E proteins HEB and E2A, hematopoietic bHLH transcription factor LYL1, LIM domain protein LMO2 and its binding partner LDB1 [6]. These AETFC components mutually stabilize each other and cooperatively bind and regulate target genes, and AETFC integrity and proper conformation are essential for leukemogenesis [6]. Thus, destabilization of AETFC provides a strategy to target AML1-ETO. Notably, it has been generally proposed that the stability of a protein complex can