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

被引:28
作者
Wang, Yin [1 ,2 ]
Liu, Yan [1 ,2 ]
Bailey, Christopher [1 ,2 ,3 ]
Zhang, Huixia [4 ]
He, Miao [4 ]
Sun, Duxin [4 ]
Zhang, Peng [1 ,2 ]
Parkin, Brian [5 ]
Baer, Maria R. [6 ]
Zheng, Pan [1 ,2 ,7 ]
Malek, Sami N. [5 ]
Liu, Yang [1 ,2 ,7 ]
机构
[1] Univ Maryland, Sch Med, Dept Surg, Div Immunotherapy,Inst Human Virol, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Ctr Comprehens Canc, Baltimore, MD 21201 USA
[3] George Washington Univ, Sch Med, Grad Program Integrated Biomed Res, Washington, DC 20052 USA
[4] Univ Michigan, Dept Pharmaceut Sci, Ann Arbor, MI 48109 USA
[5] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA
[6] Univ Maryland, Dept Med, Greenebaum Comprehens Canc Ctr, Baltimore, MD 21201 USA
[7] OncoImmune Inc, Rockville, MD 20853 USA
基金
美国国家卫生研究院;
关键词
MYELODYSPLASTIC SYNDROMES; P53; MUTATIONS; STEM-CELLS; TP53; GENE; SURVIVAL; PERMEABILITY; HIF1-ALPHA;
D O I
10.1038/s41388-020-1201-z
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-1 alpha target genes are enriched in TP53-mutated versus TP53-wild-type AML. To determine the role of this activation, we tested efficacy of HIF-1 alpha 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 IC(50)s 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.
引用
收藏
页码:3015 / 3027
页数:13
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