Tottone Luca, Zhdanovskaya Nadezda, Carmona Pestaña Álvaro, Zampieri Michele, Simeoni Fabrizio, Lazzari Sara, Ruocco Valeria, Pelullo Maria, Caiafa Paola, Felli Maria Pia, Checquolo Saula, Bellavia Diana, Talora Claudio, Screpanti Isabella, Palermo Rocco
Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.
Front Oncol. 2019 Apr 3;9:198. doi: 10.3389/fonc.2019.00198. eCollection 2019.
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive blood cancer caused by the deregulation of key T-cell developmental pathways, including Notch signaling. Aberrant Notch signaling in T-ALL occurs by gain-of-function mutations and by overexpression. Although is assumed as a Notch1 target, machinery driving its transcription in T-ALL is undefined in leukemia subsets lacking Notch1 activation. Here, we found that the binding of the intracellular Notch3 domain, as well as of the activated Notch1 fragment, to the gene locus led to the recruitment of the H3K27 modifiers JMJD3 and p300, and it was required to preserve transcriptional permissive/active H3K27 marks and to sustain gene expression levels. Consistently, pharmacological inhibition of JMJD3 by GSKJ4 treatment or of p300 by A-485 decreased the levels of expression of and of the Notch target genes and c-Myc and abrogated cell viability in both Notch1- and Notch3-dependent T-cell contexts. Notably, re-introduction of exogenous Notch1, Notch3 as well as c-Myc partially rescued cells from anti-growth effects induced by either treatment. Overall our findings indicate JMJD3 and p300 as general Notch1 and Notch3 signaling co-activators in T-ALL and suggest further investigation on the potential therapeutic anti-leukemic efficacy of their enzymatic inhibition in Notch/c-Myc axis-related cancers and diseases.
T细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血癌，由关键T细胞发育途径（包括Notch信号通路）失调引起。T-ALL中异常的Notch信号通过功能获得性突变和过表达发生。尽管假定 是Notch1的靶标，但在缺乏Notch1激活的白血病亚群中，驱动其在T-ALL中转录的机制尚不清楚。在这里，我们发现细胞内Notch3结构域以及活化的Notch1片段与 基因座的结合导致H3K27修饰因子JMJD3和p300的募集，并且这对于维持转录允许/活性H3K27标记和维持 基因表达水平是必需的。一致地，通过GSKJ4处理对JMJD3进行药理抑制或通过A-485对p300进行药理抑制，均可降低 和Notch靶基因 及c-Myc的表达水平，并消除Notch1和Notch3依赖性T细胞环境中的细胞活力。值得注意的是，重新引入外源性Notch1、Notch3以及c-Myc可部分挽救细胞免受两种处理诱导的抗生长效应。总体而言，我们的研究结果表明JMJD3和p300是T-ALL中Notch1和Notch3信号的一般共激活因子，并建议进一步研究其酶抑制在Notch/c-Myc轴相关癌症和疾病中的潜在抗白血病治疗效果。
