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Series GSE227114 Query DataSets for GSE227114
Status Public on Oct 01, 2023
Title Targeting cis-regulatory elements of FOXO family is a novel therapeutic strategy for induction of leukemia cell differentiation
Organism Homo sapiens
Experiment type Expression profiling by array
Summary 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.
Overall design Comaprison between negative control cells and FOXO inhibitor (AS1842856) treated cells. There are three biological replicates for each conditions.
Contributor(s) Kurayoshi K, Takase Y, Ueno M, Ohta K, Fuse K, Ikeda S, Watanabe T, Nishida Y, Horike S, Hosomichi K, Ishikawa Y, Tadokoro Y, Kobayashi M, Kasahara A, Jing Y, Shoulkamy MI, Meguro-Horike M, Kojima K, Kiyoi H, Sugiyama H, Nagase H, Tajima A, Hirao A
Citation(s) 37773170
Submission date Mar 10, 2023
Last update date Oct 02, 2023
Contact name Shin-ichi Horike
Phone +81-76-265-2775
Organization name Kanazawa University
Department Research Center for Experimental Modeling of Human Disease
Street address 13-1 Takaramachi
City Kanazawa
State/province Ishikawa
ZIP/Postal code 920-0934
Country Japan
Platforms (1)
GPL13497 Agilent-026652 Whole Human Genome Microarray 4x44K v2 (Probe Name version)
Samples (6)
GSM7091834 THP-1_CTL_rep1
GSM7091835 THP-1_CTL_rep2
GSM7091836 THP-1_CTL_rep3
BioProject PRJNA943247

Download family Format
SOFT formatted family file(s) SOFTHelp
MINiML formatted family file(s) MINiMLHelp
Series Matrix File(s) TXTHelp

Supplementary file Size Download File type/resource
GSE227114_RAW.tar 13.1 Mb (http)(custom) TAR (of TXT)
Processed data included within Sample table

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