Unfolded protein response (UPR) is a conserved adaptive response that tries to restore protein homeostasis after endoplasmic reticulum (ER) stress. Recent studies highlighted the role of UPR in acute leukemias and UPR targeting has been suggested as a therapeutic approach. Aberrant Notch signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL), as downregulation of Notch activity negatively affects T-ALL cell survival, leading to the employment of Notch inhibitors in T-ALL therapy. Here we demonstrate that Notch3 is able to sustain UPR in T-ALL cells, as Notch3 silencing favored a Bip-dependent IRE1α inactivation under ER stress conditions, leading to increased apoptosis via upregulation of the ER stress cell death mediator CHOP. By using Juglone, a naturally occurring naphthoquinone acting as an anticancer agent, to decrease Notch3 expression and induce ER stress, we observed an increased ER stress-associated apoptosis. Altogether our results suggest that Notch3 inhibition may prevent leukemia cells from engaging a functional UPR needed to compensate the Juglone-mediated ER proteotoxic stress. Notably, in vivo administration of Juglone to human T-ALL xenotransplant models significantly reduced tumor growth, finally fostering the exploitation of Juglone-dependent Notch3 inhibition to perturb the ER stress/UPR signaling in Notch3-dependent T-ALL subsets.

未折叠蛋白应答（UPR）是一种保守的适应性应答，试图在内质网（ER）应激后恢复蛋白稳态。最近的研究强调了UPR在急性白血病中的作用，并且已提出将UPR靶向作为治疗方法。Notch信号异常是T细胞急性淋巴细胞白血病（T-ALL）的共同特征，因为Notch活性的下调会对T-ALL细胞的存活产生负面影响，从而导致在Notch抑制剂中使用Notch抑制剂。在这里，我们证明Notch3能够在T-ALL细胞中维持UPR，因为Notch3沉默有利于ER应激条件下依赖Bip的IRE1α失活，从而通过上调ER应激细胞死亡介导物CHOP导致凋亡增加。通过使用Juglone，一种天然的萘醌作为抗癌剂，可降低Notch3表达并诱导内质网应激，我们观察到内质网应激相关的细胞凋亡增加。总之，我们的结果表明，Notch3抑制作用可能阻止白血病细胞参与补偿Juglone介导的ER蛋白毒性压力所需的功能性UPR 。值得注意的是，向人T-ALL异种移植模型体内施用Juglone显着降低了肿瘤的生长，最终促进了对Juglone依赖性Notch3抑制作用的开发，以扰动Notch3依赖性T-ALL亚型中的ER应激/ UPR信号传导。