Targeting cis-regulatory elements of FOXO family is a novel therapeutic strategy for induction of leukemia cell differentiation

• Published in: Cell death & disease Vol. 14; no. 9; p. 642
• Main 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, Nagase, Hiroki, Tajima, Atsushi, Hirao, Atsushi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 29.09.2023; Springer Nature B.V; Nature Publishing Group
• Subjects: 38; 38/61; 45; 45/15; 45/41; 45/77; 631/80/304; 692/699/67/1059/153; Acute myeloid leukemia; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Cell differentiation; Chlorambucil; CRISPR; Forkhead protein; FOXO3 protein; Gene expression; Imidazole; Immunology; Leukemia; Life Sciences; Polyamides; Regulatory sequences; Therapeutic targets; Ubiquitin-protein ligase
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-023-06168-2

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.