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Therapeutic targeting of the E3 ubiquitin ligase SKP2 in T-ALL.
Leukemia ( IF 11.4 ) Pub Date : 2019-11-26 , DOI: 10.1038/s41375-019-0653-z
Sonia Rodriguez 1, 2 , Christina Abundis 1 , Francesco Boccalatte 3 , Purvi Mehrotra 2 , Mark Y Chiang 4 , Mary A Yui 5 , Lin Wang 2, 6 , Huajia Zhang 2, 7 , Amy Zollman 2 , Ricardo Bonfim-Silva 2, 8 , Andreas Kloetgen 3 , Joycelynne Palmer 1 , George Sandusky 6 , Mark Wunderlich 9 , Mark H Kaplan 2 , James C Mulloy 9 , Guido Marcucci 1 , Iannis Aifantis 3 , Angelo A Cardoso 1 , Nadia Carlesso 1, 2
Affiliation  

Timed degradation of the cyclin-dependent kinase inhibitor p27Kip1 by the E3 ubiquitin ligase F-box protein SKP2 is critical for T-cell progression into cell cycle, coordinating proliferation and differentiation processes. SKP2 expression is regulated by mitogenic stimuli and by Notch signaling, a key pathway in T-cell development and in T-cell acute lymphoblastic leukemia (T-ALL); however, it is not known whether SKP2 plays a role in the development of T-ALL. Here, we determined that SKP2 function is relevant for T-ALL leukemogenesis, whereas is dispensable for T-cell development. Targeted inhibition of SKP2 by genetic deletion or pharmacological blockade markedly inhibited proliferation of human T-ALL cells in vitro and antagonized disease in vivo in murine and xenograft leukemia models, with little effect on normal tissues. We also demonstrate a novel feed forward feedback loop by which Notch and IL-7 signaling cooperatively converge on SKP2 induction and cell cycle activation. These studies show that the Notch/SKP2/p27Kip1 pathway plays a unique role in T-ALL development and provide a proof-of-concept for the use of SKP2 as a new therapeutic target in T-cell acute lymphoblastic leukemia (T-ALL).

中文翻译:

E3泛素连接酶SKP2在T-ALL中的治疗靶向。

E3泛素连接酶F-box蛋白SKP2对细胞周期蛋白依赖性激酶抑制剂p27Kip1的及时降解对于T细胞进入细胞周期,协调增殖和分化过程至关重要。SKP2的表达受促有丝分裂刺激和Notch信号调节,Notch信号是T细胞发育和T细胞急性淋巴细胞白血病(T-ALL)的关键途径。然而,未知SKP2是否在T-ALL的发展中发挥作用。在这里,我们确定SKP2功能与T-ALL白血病发生有关,而对于T细胞发育却是必不可少的。在小鼠和异种移植性白血病模型中,通过基因删除或药理学封锁有针对性地抑制SKP2可以显着抑制人T-ALL细胞的增殖,并在体内拮抗体内疾病,对正常组织的影响很小。我们还展示了一种新颖的前馈反馈环,通过该环,Notch和IL-7信号协同收敛于SKP2诱导和细胞周期激活。这些研究表明,Notch / SKP2 / p27Kip1途径在T-ALL的发展中起着独特的作用,并为将SKP2用作T细胞急性淋巴细胞白血病(T-ALL)的新治疗靶点提供了概念验证。 。
更新日期:2019-11-27
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