Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes
Yingwan Luo, … , Gang Huang, Hongyan Tong
Yingwan Luo, … , Gang Huang, Hongyan Tong
Published February 22, 2024
Citation Information: J Clin Invest. 2024;134(8):e172468. https://doi.org/10.1172/JCI172468.
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Research Article Hematology

Ectopic expression of the transcription factor ONECUT3 drives a complex karyotype in myelodysplastic syndromes

Abstract

Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.

Authors

Yingwan Luo, Xiaomin Feng, Wei Lang, Weihong Xu, Wei Wang, Chen Mei, Li Ye, Shuanghong Zhu, Lu Wang, Xinping Zhou, Huimin Zeng, Liya Ma, Yanling Ren, Jie Jin, Rongzhen Xu, Gang Huang, Hongyan Tong

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Figure 6

Schematic model depicting highly expressed ONECUT3 causing mitotic defects through upregulation of the CPC.

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Schematic model depicting highly expressed ONECUT3 causing mitotic defec...
(A) By modulating the levels of INCENP and CDCA8, ONECUT3 controlled the mitotic process, thereby ensuring the maintenance of a NK and enhancing sensitivity to drugs. (B) OE of ONECUT3 led to its binding to the genome of INCENP and CDCA8, resulting in the excessive activation of CPC component expression. Dysregulation of the CPC subsequently gave rise to mitotic defects, such as multipolar and chromosome missegregations, leading to the development of a CK and reduced sensitivity to drugs. (C) A lead compound, C5484617, was identified that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. It was worth noting that ONECUT3-overexpressing cells displayed chemoresistance, which could be partially alleviated through the use of compounds that target the ONECUT3/CPC axis, such as C5484617 or barasertib.