HSP90 is a therapeutic target independent of TP53 gene mutation status, and the epichaperome is present in TP53-mutant AML cells and AML stem/progenitor cells. (A) High-throughput screening of ∼2400 approved drugs identified ∼200 compounds with activity in TP53-WT, TP53-R248Q, and TP53-R175H Molm13 cells independent of TP53 mutation status (left, red indicates HSP90 inhibitors). The error bars are the SEM of AOC_LD of the 3 cell lines. Three agents targeting HSP90 are top hits (right). Viable cell counts were normalized to the median cell count at the time of drug addition. A value of 1 represents negative control-like growth, values between 0 and 1 represent cyto-suppression, and negative values denote loss of cells from baseline. (B-D) The epichaperome was identified in Molm13 cells with variable TP53 status: (B) (left) a representative experiment and (right) quantification of triplicate experiments in primary AML cells and stem progenitor cells from patients; (C) a representative result from a patient with TP53-mutation (left) and results from TP53-mutant (right), TP53-/RAS-mutant, or kinase-mutant samples and samples without TP53/kinase mutations; and in normal BM controls (D). The epichaperome was identified via flow cytometry using FITC-labeled PU-H71 as probe. AOC_LD, area over the curve lethal dose; MFI, mean fluorescence intensity; SEM, standard error of the mean.