Department of Hematology and Oncology, Children's Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
Cell Death Dis. 2024 Sep 4;15(9):646. doi: 10.1038/s41419-024-07040-7.
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.
T 细胞急性淋巴细胞白血病（T-ALL）是一种侵袭性血液系统恶性肿瘤，常见于儿童和青少年，预后较差。未折叠蛋白反应（UPR）是一种新兴的抗癌方法，但在儿科 T-ALL 中的作用尚不清楚。在来自不同中心的儿科 T-ALL 队列中，我们发现 QRICH1 表达较低与儿科 T-ALL 的预后较差相关。QRICH1 的过表达显著抑制 T-ALL 细胞的体外和体内增殖，并刺激细胞凋亡。上调 QRICH1 可显著下调 78 kDa 葡萄糖调节蛋白（GRP78），上调 CHOP，从而激活末端 UPR。在过表达 QRICH1 的 T-ALL 细胞中共同过表达 GRP78 部分逆转了抑制增殖和刺激凋亡的作用。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）应激有关，过表达 QRICH1 可逆转耐药性。总的来说，QRICH1 表达水平低是儿科 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。
