T 细胞急性淋巴细胞白血病 (T-ALL) 是一种侵袭性血液恶性肿瘤，通常影响儿童和青少年，预后不良。终末未折叠蛋白反应 (UPR) 是一种新兴的抗癌方法，但其在儿科 T-ALL 中的作用仍不清楚。在我们来自不同中心的儿科 T-ALL 队列中，发现 QRICH1 表达较低与儿科 T-ALL 预后较差相关。 QRICH1 的过表达在体外和体内均显着抑制 T-ALL 细胞增殖并刺激细胞凋亡。 QRICH1 的上调显着下调 78 KDa 葡萄糖调节蛋白 (GRP78) 并上调 CHOP，从而激活末端 UPR。在过表达 QRICH1 的 T-ALL 细胞中，GRP78 的共过表达可部分恢复受抑制的增殖并刺激细胞凋亡。 QRICH1与GRP78的核苷酸结合域（NBD）的残基Asp212和Glu155结合，从而抑制其ATP水解活性。此外，QRICH1与T-ALL中的内质网（ER）应激相关，并且QRICH1的过度表达可逆转耐药性。总体而言，QRICH1低表达是儿童T-ALL预后不良的独立危险因素。通过抑制 GRP78，QRICH1 抑制儿科 T-ALL。© 2024。作者。

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy that commonly affects children and adolescents with a poor prognosis. The terminal unfolded protein response (UPR) is an emerging anti-cancer approach, although its role in pediatric T-ALL remains unclear. In our pediatric T-ALL cohort from different centers, a lower QRICH1 expression was found associated with a worse prognosis of pediatric T-ALL. Overexpression of QRICH1 significantly inhibited cell proliferation and stimulated apoptosis of T-ALL both in vitro and in vivo. Upregulation of QRICH1 significantly downregulated 78 KDa glucose-regulated protein (GRP78) and upregulated CHOP, thus activating the terminal UPR. Co-overexpression of GRP78 in T-ALL cells overexpressing QRICH1 partially reverted the inhibited proliferation and stimulated apoptosis. QRICH1 bound to the residues Asp212 and Glu155 of the nucleotide-binding domain (NBD) of GRP78, thereby inhibiting its ATP hydrolysis activity. In addition, QRICH1 was associated with endoplasmic reticulum (ER) stress in T-ALL, and overexpression of QRICH1 reversed drug resistance. Overall, low QRICH1 expression is an independent risk factor for a poor prognosis of pediatric T-ALL. By inhibiting GRP78, QRICH1 suppresses pediatric T-ALL.© 2024. The Author(s).