QRICH1 suppresses pediatric T-cell acute lymphoblastic leukemia by inhibiting GRP78

TL;DR

QRICH1 helps fight pediatric T-cell leukemia by inhibiting GRP78, improving prognosis and reducing drug resistance.

Contribution

QRICH1 is identified as a novel suppressor of pediatric T-ALL through GRP78 inhibition and UPR activation.

Findings

Low QRICH1 expression correlates with poor prognosis in pediatric T-ALL.

QRICH1 inhibits T-ALL cell proliferation and induces apoptosis by downregulating GRP78.

QRICH1 reverses drug resistance and activates the terminal UPR in T-ALL.

Abstract

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.

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