Preclinical testing of CT1113, a novel USP28 inhibitor, for the treatment of T‐cell acute lymphoblastic leukaemia

Abstract

SummaryT‐cell acute lymphoblastic leukaemia (T‐ALL) is a highly aggressive and heterogeneous lymphoid malignancy with poor prognosis in adult patients. Aberrant activation of the NOTCH1 signalling pathway is involved in the pathogenesis of over 60% of T‐ALL cases. Ubiquitin‐specific protease 28 (USP28) is a deubiquitinase known to regulate the stability of NOTCH1. Here, we report that genetic depletion of USP28 or using CT1113, a potent small molecule targeting USP28, can strongly destabilize NOTCH1 and inhibit the growth of T‐ALL cells. Moreover, we show that USP28 also regulates the stability of sterol regulatory element binding protein 1 (SREBP1), which has been reported to mediate increased lipogenesis in tumour cells. As the most critical transcription factor involved in regulating lipogenesis, SREBP1 plays an important role in the metabolism of T‐ALL. Therefore, USP28 may be a potential therapeutic target, and CT1113 may be a promising novel drug for T‐ALL with or without mutant NOTCH1.