Dual inhibition of EZH1/2 induces cell cycle arrest of B cell acute lymphoblastic leukemia cells through upregulation of CDKN1C and TP53INP1

by Selleckchem | Sep 09 2023

Disease-risk stratification and development of intensified chemotherapy protocols have substantially improved the outcome of acute lymphoblastic leukemia (ALL). However, outcomes of relapsed or refractory cases remain poor. Previous studies have discussed the oncogenic role of enhancer of zeste homolog 1 and 2 (EZH1/2), and the efficacy of dual inhibition of EZH1/2 as a treatment for hematological malignancy. Here, we investigated whether an EZH1/2 dual inhibitor, DS-3201 (valemetostat), has antitumor effects on B cell ALL (B-ALL). DS-3201 inhibited growth of B-ALL cell lines more significantly and strongly than the EZH2-specific inhibitor EPZ-6438, and induced cell cycle arrest and apoptosis in vitro. RNA-seq analysis to determine the effect of DS-3201 on cell cycle arrest-related genes expressed by B-ALL cell lines showed that DS-3201 upregulated CDKN1C and TP53INP1. CRIPSR/Cas9 knockout confirmed that CDKN1C and TP53INP1 are direct targets of EZH1/2 and are responsible for the antitumor effects of DS-3201 against B-ALL. Furthermore, a patient-derived xenograft (PDX) mouse model showed that DS-3201 inhibited the growth of B-ALL harboring MLL-AF4 significantly. Thus, DS-3201 provides another option for treatment of B-ALL.

Comments:

The research you described focuses on investigating the potential therapeutic effects of an EZH1/2 dual inhibitor called DS-3201 (valemetostat) on B cell acute lymphoblastic leukemia (B-ALL). The study aimed to determine whether DS-3201 could effectively inhibit the growth of B-ALL cells and induce cell cycle arrest and apoptosis.

The researchers compared the efficacy of DS-3201 with EPZ-6438, an EZH2-specific inhibitor, in inhibiting the growth of B-ALL cell lines. They found that DS-3201 exhibited more significant and potent inhibition of B-ALL cell line growth than EPZ-6438. Additionally, DS-3201 induced cell cycle arrest and apoptosis in vitro.

To gain insights into the molecular mechanisms underlying the antitumor effects of DS-3201, the researchers performed RNA-seq analysis. They focused on cell cycle arrest-related genes expressed by B-ALL cell lines and discovered that DS-3201 upregulated the expression of CDKN1C and TP53INP1. Subsequent CRISPR/Cas9 knockout experiments confirmed that CDKN1C and TP53INP1 are direct targets of EZH1/2 and are responsible for the observed antitumor effects of DS-3201 in B-ALL.

Moreover, the researchers tested the efficacy of DS-3201 in a patient-derived xenograft (PDX) mouse model carrying MLL-AF4, a genetic alteration commonly found in B-ALL. The results demonstrated that DS-3201 effectively inhibited the growth of B-ALL tumors harboring MLL-AF4 in the PDX model.

Based on these findings, the study suggests that DS-3201, as an EZH1/2 dual inhibitor, could offer a potential treatment option for B-ALL, including cases that have relapsed or become refractory to standard therapies. The research highlights the importance of targeting EZH1/2 and identifies CDKN1C and TP53INP1 as key mediators of the antitumor effects of DS-3201 in B-ALL. Further investigations and clinical trials are needed to validate these findings and determine the efficacy and safety of DS-3201 as a therapeutic agent for B-ALL.