Therapeutic targeting of TP53-mutated acute myeloid leukemia by inhibiting HIF-1α with echinomycin.

ABSTRACT: TP53 mutation in acute myeloid leukemia (AML) is associated with poor prognosis. Since no targeted therapy is available to restore p53 function, it is of great interest to test whether other pathways activated by TP53 mutations can be therapeutically targeted. Here, we showed HIF-1α target genes are enriched in TP53-mutated versus TP53-wild-type AML. To determine the role of this activation, we tested efficacy of HIF-1α inhibitor echinomycin in TP53-mutated AML samples in vitro and in vivo. Echinomycin was broadly effective against a panel of primary AML blast cells, with low nanomolar IC₅₀s and, based on colony-forming unit assay, was tenfold more effective in eliminating AML stem cells. Echinomycin selectively eliminated CD34⁺CD38^- AML cells. To test the

SUBMITTER: Wang Y 

PROVIDER: S-EPMC7291851 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature