ENHANCING EXPRESSION OF PRO-APOPTOTIC FACTORS THROUGH INHIBITION OF HDACS DRIVES P53-INDEPENDENT SYNERGY WITH VENETOCLAX FOR THE TREATMENT OF AML

Abstract

Targeting BCL-2 with the BH3-mimetic venetoclax (VEN) has emerged as a highly efficacious treatment for elderly patients with acute myeloid leukaemia (AML), in combination with either low-dose Ara-C (Wei, JCO 2019) or hypomethylating agents (Di Nardo, Lancet Oncol 2018). Long-term survival outcomes remain poor among patients with adverse risk karyotype, who often harbour mutations in the TP53 gene. Therefore, identification of effective treatment options, with TP53 independent activity, represents an area of high unmet therapeutic need. We generated TP53-null AML cell lines using CRISPR-Cas9 gene editing and screened these cell lines against 48 compounds. The histone deacetylase inhibitors (..