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Theranostics 2018; 8(8):2189-2201. doi:10.7150/thno.22800 This issue Cite

Research Paper

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

Lianghao Lu^1,†, Yefei Wen^1,†, Yuan Yao¹, Fengju Chen², Guohui Wang¹, Fangrui Wu¹, Jingyu Wu¹, Padmini Narayanan^3,4, Michele Redell^3,4, Qianxing Mo^2,5, Yongcheng Song^1,2,✉

1. Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
2. Dan L. Duncan Cancer Center, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
3. Department of Pediatrics, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
4. Texas Children's Cancer and Hematology Centers, 1102 Bates Street, Houston, TX 77030, USA.
5. Department of Medicine, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, USA.
^† These authors contributed equally.

✉ Corresponding author: Address: Department of Pharmacology and Chemical Biology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030. Tel: 713-798-7415. E-mail: ysongedu.

Abstract

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 ~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.

Keywords: Acute myeloid leukemia, chromosome translocation t(8, 21), RUNX1-ETO, Glucocorticoid, Glucocorticoid receptor, Targeted therapy

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