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GEO help: Mouse over screen elements for information. |
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| 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
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| 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.
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| Overall design |
Comaprison between negative control cells and FOXO inhibitor (AS1842856) treated cells. There are three biological replicates for each conditions.
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| 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 |
| E-mail(s) |
sihorike@staff.kanazawa-u.ac.jp
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| Phone |
+81-76-265-2775
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| Organization name |
Kanazawa University
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| Department |
Research Center for Experimental Modeling of Human Disease
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| Lab |
HORIKE Lab
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| Street address |
13-1 Takaramachi
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| City |
Kanazawa |
| State/province |
Ishikawa |
| ZIP/Postal code |
920-0934 |
| Country |
Japan |
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| Platforms (1) |
| GPL13497 |
Agilent-026652 Whole Human Genome Microarray 4x44K v2 (Probe Name version) |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA943247 |
| 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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