Dinaciclib reduces MCL-1 levels and triggers apoptosis in adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is a rare T-cell malignancy caused by long-term HTLV-1 infection. The disease is aggressive, with a median survival of 8-10 months, and no new treatments are currently available. Dinaciclib is a selective small-molecule drug that targets CDK1, CDK2, CDK5, and CDK9. This study assessed dinaciclib's ability to inhibit ATL cells. It significantly suppressed ATL proliferation at low nanomolar concentrations. The antiproliferative effect was due to induced apoptotic cell death, as shown by FACS analysis. Annexin/PI staining revealed morphological signs of apoptosis after dinaciclib treatment, while pre-treatment with Q-VD-OPh prevented apoptosis in ATL cells. The primary mechanism by which dinaciclib induces apoptosis appears to involve deregulation of anti-apoptotic proteins, especially MCL-1. MCL-1 protein levels decreased significantly in a dose- and time-dependent manner, coinciding with caspase-3 activation. The anti-tumor effects of dinaciclib were confirmed in an in vivo xenograft model. Overall, this study demonstrates that dinaciclib effectively targets ATL cells by inducing MCL-1 deregulation and promoting apoptotic cell death.