Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells.
Autonomous feedback loop of RUNX1-p53-CBFB in acute myeloid leukemia cells.
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DOI：
10.1038/s41598-017-16799-z
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发表时间：
2017-11-30
影响因子：
4.6
通讯作者：
Kamikubo Y
中科院分区：
文献类型：
--
作者：
Morita K;Noura M;Tokushige C;Maeda S;Kiyose H;Kashiwazaki G;Taniguchi J;Bando T;Yoshida K;Ozaki T;Matsuo H;Ogawa S;Liu PP;Nakahata T;Sugiyama H;Adachi S;Kamikubo Y
尽管RUNX 1及其相关的核心结合因子-β（CBFB）在白血病发生中起着关键作用，抑制RUNX 1已被广泛认为是一种抗白血病治疗的新策略，但白血病细胞如何对RUNX 1抑制剂产生严重耐药性以及CBFB是否参与了这一过程一直是个谜。在这里，我们证明了p53（TP 53）和CBFB在响应RUNX 1耗竭时顺序上调的证据，它们的相互作用导致急性髓系白血病（AML）细胞对化疗的生理抗性。从机制上讲，RUNX 1基因沉默诱导的p53直接结合CBFB启动子并刺激其转录和翻译，而CBFB启动子又作为RUNX 1稳定的平台，从而形成补偿性RUNX 1-p53-CBFB反馈循环。事实上，与诊断时的原代AML细胞相比，来自复发病例的AML细胞表现出更高的CBFB表达水平，并且这些CBFB表达与p53的表达正相关。我们目前的研究结果强调了RUNX 1-p53-CBFB调控环在AML细胞发育和/或维持中的重要性，这可以在制定抗白血病治疗策略时靶向这个三角形的任何一边。
Although runt-related transcription factor 1 (RUNX1) and its associating core binding factor-β (CBFB) play pivotal roles in leukemogenesis, and inhibition of RUNX1 has now been widely recognized as a novel strategy for anti-leukemic therapies, it has been elusive how leukemic cells could acquire the serious resistance against RUNX1-inhibition therapies and also whether CBFB could participate in this process. Here, we show evidence that p53 (TP53) and CBFB are sequentially up-regulated in response to RUNX1 depletion, and their mutual interaction causes the physiological resistance against chemotherapy for acute myeloid leukemia (AML) cells. Mechanistically, p53 induced by RUNX1 gene silencing directly binds to CBFB promoter and stimulates its transcription as well as its translation, which in turn acts as a platform for the stabilization of RUNX1, thereby creating a compensative RUNX1-p53-CBFB feedback loop. Indeed, AML cells derived from relapsed cases exhibited higher CBFB expression levels compared to those from primary AML cells at diagnosis, and these CBFB expressions were positively correlated to those of p53. Our present results underscore the importance of RUNX1-p53-CBFB regulatory loop in the development and/or maintenance of AML cells, which could be targeted at any sides of this triangle in strategizing anti-leukemia therapies.
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