CEBP-Beta/IL-1-Beta/ TNF-alpha Feedback Loop Drives Drug Resistance to BCL2 and MDM2 Inhibitors in Monocytic Leukemia Cells

To uncover the mechanisms of MDM2 inhibitor resistance that are mediated by IL-1, we performed RNAseq on three primary AML patient cells treated with idasanutlin in the presence or absence of IL-1beta. These three leukemia samples were chosen because they exhibit high blast counts and are protected by IL-1beta when treated with idasanutlin, as determined by apoptosis assay. We observed that a majority of the major p53 pathway targets remained upregulated in the presence of IL-1beta. We next performed differential expressed gene (DEG) analysis following IL-1beta treatment with and without idasanutlin. IL-1beta treatment upregulated 3295, 1353, and 680 genes with >=1 Log2FC, in each of the three patient samples, and a significant majority of these genes (82%, 62.4%, and 47.6%)... (for more see dbGaP study page.)