Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation.
Heterodimerization of AML1/ETO with CBFβ is required for leukemogenesis but not for myeloproliferation.
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DOI：
10.1038/leu.2017.105
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发表时间：
2017-11
期刊：
影响因子：
11.4
通讯作者：
Oswald F
中科院分区：
文献类型：
--
作者：
Thiel VN;Giaimo BD;Schwarz P;Soller K;Vas V;Bartkuhn M;Blätte TJ;Döhner K;Bullinger L;Borggrefe T;Geiger H;Oswald F
AML1/RUNX1转录因子及其异源二聚体CbFβ是髓系分化的重要调控因子。染色体易位t(8；21)将AML1的DNA结合域与辅阻遏子8-21(ETO)融合，常与急性髓系白血病相关，并产生AML1/ETO(AE)融合蛋白。AE抑制通常由AML1激活的靶基因，也影响ETO在Notch靶基因上的内源性抑制功能。为了分析Cbfβ在AE介导的白血病发生和Notch靶基因失控中的作用，我们在小鼠白血病启动版本AE9a中引入了两个点突变，它们破坏了AML1/Cbfβ相互作用(AE9aNT)。我们报道，AE9a/Cbfβ的相互作用不是AE9a介导的AML1基因异常表达所必需的，而Notch靶基因的上调/下调确实需要与Cbfβ的相互作用。利用逆转录病毒转导技术在小鼠骨髓来源的造血祖细胞中表达AE9a，我们观察到AE9a和AE9aNT在体内均能促进骨髓增殖。然而，AE9a只观察到白血病的发展和长期复制能力，而AE9aNT没有观察到。因此，AML1和Notch靶基因的解除调控对于AE9a驱动的白血病的发展是必要的。
The AML1/Runx1 transcription factor and its heterodimerization partner CBFβ are essential regulators of myeloid differentiation. The chromosomal translocation t(8;21), fusing the DNA binding domain of AML1 to the corepressor eight-twenty-one (ETO), is frequently associated with acute myeloid leukemia and generates the AML1/ETO (AE) fusion protein. AE represses target genes usually activated by AML1 and also affects the endogenous repressive function of ETO at Notch target genes. In order to analyze the contribution of CBFβ in AE-mediated leukemogenesis and deregulation of Notch target genes, we introduced two point mutations in a leukemia-initiating version of AE in mice, called AE9a, that disrupt the AML1/CBFβ interaction (AE9aNT). We report that the AE9a/CBFβ interaction is not required for the AE9a-mediated aberrant expression of AML1 target genes, while upregulation/derepression of Notch target genes does require the interaction with CBFβ. Using retroviral transduction to express AE9a in murine adult bone marrow-derived hematopoietic progenitors, we observed that both AE9a and AE9aNT lead to increased myeloproliferation in vivo. However, both development of leukemia and long-term replating capacity are only observed with AE9a but not with AE9aNT. Thus, deregulation of both AML1 and Notch target genes is required for the development of AE9a-driven leukemia.
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影响因子：
3.2
作者：
Chiang MY;Radojcic V;Maillard I
通讯作者：
Maillard I
DOI：
10.2741/3977
发表时间：
2012-01-01
期刊：
Frontiers in bioscience (Landmark edition)
影响因子：
--
作者：
Lam K;Zhang DE
通讯作者：
Zhang DE
DOI：
10.1084/jem.20121484
发表时间：
2013-02-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lobry C;Ntziachristos P;Ndiaye-Lobry D;Oh P;Cimmino L;Zhu N;Araldi E;Hu W;Freund J;Abdel-Wahab O;Ibrahim S;Skokos D;Armstrong SA;Levine RL;Park CY;Aifantis I
通讯作者：
Aifantis I
DOI：
10.1073/pnas.0810558106
发表时间：
2009-02-24
影响因子：
11.1
作者：
Kwok, Colin;Zeisig, Bernd B.;So, Chi Wai Eric
通讯作者：
So, Chi Wai Eric
影响因子：
--
作者：
Gorczynski, Michael J.;Grembecka, Jolanta;Bushweller, John H.
通讯作者：
Bushweller, John H.