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- Title
Targeting cis-regulatory elements of FOXO family is a novel therapeutic strategy for induction of leukemia cell differentiation.
- Authors
Kurayoshi, Kenta; Takase, Yusuke; Ueno, Masaya; Ohta, Kumiko; Fuse, Kyoko; Ikeda, Shuji; Watanabe, Takayoshi; Nishida, Yuki; Horike, Shin-ichi; Hosomichi, Kazuyoshi; Ishikawa, Yuichi; Tadokoro, Yuko; Kobayashi, Masahiko; Kasahara, Atsuko; Jing, Yongwei; Shoulkamy, Mahmoud I.; Meguro-Horike, Makiko; Kojima, Kensuke; Kiyoi, Hitoshi; Sugiyama, Hiroshi
- Abstract
Differentiation therapy has been proposed as a promising therapeutic strategy for acute myeloid leukemia (AML); thus, the development of more versatile methodologies that are applicable to a wide range of AML subtypes is desired. Although the FOXOs transcription factor represents a promising drug target for differentiation therapy, the efficacy of FOXO inhibitors is limited in vivo. Here, we show that pharmacological inhibition of a common cis-regulatory element of forkhead box O (FOXO) family members successfully induced cell differentiation in various AML cell lines. Through gene expression profiling and differentiation marker-based CRISPR/Cas9 screening, we identified TRIB1, a complement of the COP1 ubiquitin ligase complex, as a functional FOXO downstream gene maintaining an undifferentiated status. TRIB1 is direct target of FOXO3 and the FOXO-binding cis-regulatory element in the TRIB1 promoter, referred to as the FOXO-responsive element in the TRIB1 promoter (FRE-T), played a critical role in differentiation blockade. Thus, we designed a DNA-binding pharmacological inhibitor of the FOXO-FRE-T interface using pyrrole-imidazole polyamides (PIPs) that specifically bind to FRE-T (FRE-PIPs). The FRE-PIPs conjugated to chlorambucil (FRE-chb) inhibited transcription of TRIB1, causing differentiation in various AML cell lines. FRE-chb suppressed the formation of colonies derived from AML cell lines but not from normal counterparts. Administration of FRE-chb inhibited tumor progression in vivo without remarkable adverse effects. In conclusion, targeting cis-regulatory elements of the FOXO family is a promising therapeutic strategy that induces AML cell differentiation.
- Publication
Cell Death & Disease, 2023, Vol 14, Issue 9, p1
- ISSN
2041-4889
- Publication type
Article
- DOI
10.1038/s41419-023-06168-2