Glucocorticoids Inhibit Oncogenic RUNX1-ETO in Acute Myeloid Leukemia with Chromosome Translocation t(8;21)

被引:12
作者
Lu, Lianghao [1 ]
Wen, Yefei [1 ]
Yao, Yuan [1 ]
Chen, Fengju [2 ]
Wang, Guohui [1 ]
Wu, Fangrui [1 ]
Wu, Jingyu [1 ]
Narayanan, Padmini [3 ,4 ,5 ]
Redell, Michele [3 ,4 ,5 ]
Mo, Qianxing [2 ,6 ]
Song, Yongcheng [1 ,2 ]
机构
[1] Baylor Coll Med, Dept Pharmacol & Chem Biol, 1 Baylor Plaza, Houston, TX 77030 USA
[2] Baylor Coll Med, Dan L Duncan Canc Ctr, 1 Baylor Plaza, Houston, TX 77030 USA
[3] Baylor Coll Med, Dept Pediat, 1 Baylor Plaza, Houston, TX 77030 USA
[4] Texas Childrens Canc Ctr, 1102 Bates St, Houston, TX 77030 USA
[5] Texas Childrens Hematol Ctr, 1102 Bates St, Houston, TX 77030 USA
[6] Baylor Coll Med, Dept Med, 1 Baylor Plaza, Houston, TX 77030 USA
来源
THERANOSTICS | 2018年 / 8卷 / 08期
关键词
Acute myeloid leukemia; chromosome translocation t(8; 21); RUNX1-ETO; Glucocorticoid; Glucocorticoid receptor; Targeted therapy; TRANSCRIPTION FACTOR; RUNT DOMAIN; EMBRYONIC LETHALITY; CONNECTIVITY MAP; GENE-EXPRESSION; SELF-RENEWAL; CELL-LINES; AML1-ETO; DIFFERENTIATION; RECEPTOR;
D O I
10.7150/thno.22800
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Acute myeloid leukemia (AML) is a major blood cancer with poor prognosis. New therapies are needed to target oncogene-driven leukemia stem cells, which account for relapse and resistance. Chromosome translocation t(8;21), which produces RUNX1-ETO (R-E) fusion oncoprotein, is found in similar to 13% AML. R-E dominance negatively inhibits global gene expression regulated by RUNX1, a master transcription factor for hematopoiesis, causing increased self-renewal and blocked cell differentiation of hematopoietic progenitor cells, and eventually leukemia initiation. Methods: Connectivity-Map followed by biological activity testing were used to identify candidate compounds that can inhibit R-E-mediated gene transcription. Molecular mechanistic studies were also performed. Results: Glucocorticoid drugs, such as betamethasone and dexamethasone, were found to exhibit potent and selective in vitro and in vivo activities against R-E leukemia, as well as strong synergy when combined with chemotherapeutics. Microarray analysis showed that treatment with glucocorticoids significantly inhibited R-E's activity and reactivated that of RUNX1. Such gene expression changes caused differentiation and apoptosis of R-E leukemia cells. Our studies also show a possible molecular mechanism for the targeted therapy. Upon treatment with a glucocorticoid drug, more glucocorticoid receptor (GR) was translocated into the nucleus and bound to DNA, including promoters of RUNX1 target genes. GR was found to associate with RUNX1, but not R-E. This interaction increased binding of RUNX1 to DNA and reduced that of R-E, shifting to a RUNX1 dominance. Conclusion: Glucocorticoid drugs represent a targeted therapy for AML with chromosome translocation t(8:21). Given their high activity, favorable human pharmacokinetics as well as synergy with chemotherapeutics, glucocorticoids could be clinically useful to treat R-E AML.
引用
收藏
页码:2189 / 2201
页数:13
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