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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 therapeutic efficacy of echinomycin, we established a xenograft model of TP53-mutated AML. Echinomycin was broadly effective against xenografts from multiple AML samples in vivo, and more effective than cytarabine + daunorubicin chemotherapy. Importantly, while cytarabine + daunorubicin enriched for AML stem cells, echinomycin nearly eliminated this population. Using TP53-mutated AML cell line THP1 and patient-derived AML cells, we tested a new echinomycin formulation with longer half-life and significantly improved therapeutic effect. Our data suggest a novel approach to treat AML with TP53 mutations.

journal_name

Oncogene

journal_title

Oncogene

authors

Wang Y,Liu Y,Bailey C,Zhang H,He M,Sun D,Zhang P,Parkin B,Baer MR,Zheng P,Malek SN,Liu Y

doi

10.1038/s41388-020-1201-z

subject

Has Abstract

pub_date

2020-04-01 00:00:00

pages

3015-3027

issue

14

eissn

0950-9232

issn

1476-5594

pii

10.1038/s41388-020-1201-z

journal_volume

39

pub_type

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