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Disruption of CTCF Boundary at HOXA Locus Promote BET Inhibitors’ Therapeutic Sensitivity in Acute Myeloid Leukemia

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Abstract

Both HOX gene expression and CTCF regulation have been well demonstrated to play a critical role in regulating maintenance of leukemic stem cells (LSCs) that are known to be resistant to BET inhibitor (BETi). To investigate the regulatory role of CTCF boundary in aberrant HOX gene expression and the therapeutic sensitivity of BETi in AML, we employed CRISPR-Cas9 genome editing technology to delete 47 base pairs of the CTCF binding motif which is located between HOXA7 and HOXA9 genes (CBS7/9) in different subtypes of AML with either MLL-rearrangement or NPM1 mutation. Our results revealed that HOXA9 is significantly downregulated in response to the CBS7/9 deletion. Moreover, CBS7/9 boundary deletion sensitized the BETi treatment reaction in both MOLM-13 and OCI-AML3 cells. To further examine whether BETi therapeutic sensitivity in AML is depended on the expression level of the HOXA9 gene, we overexpressed the HOXA9 in the CBS7/9 deleted AML cell lines, which can rescue and restore the resistance to BETi treatment of the CBS7/9 KO cells by activating MAPK signaling pathway. Deletion of CBS7/9 specifically decreased the recruitment of BRD4 and RNA pol II to the posterior HOXA genes, in which, a transcription elongation factor ELL3 is the key factor in regulating HOXA gene transcription monitored by CBS7/9 chromatin boundary. Thus, disruption of CBS7/9 boundary perturbs HOXA9 transcription and regulates BETi sensitivity in AML treatment. Moreover, alteration of CTCF boundaries in the oncogene loci may provide a novel strategy to overcome the drug resistance of LSCs.

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Data Availability

The datasets and materials analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was financially supported by National Nature Science Foundation of China, PR China (No. 81800163).

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Authors and Affiliations

  1. Department of Hematology, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, 55 Zhenhai Road, Xiamen, 361003, Fujian, China

    Jie Zha, Qian Lai, Manman Deng, Haijun Zhao, Qinwei Chen & Bing Xu

  2. Key Laboratory for Diagnosis and Treatment of Hematological Malignancy of Xiamen, Xiamen, 361003, China

    Jie Zha, Qian Lai, Manman Deng, Haijun Zhao, Qinwei Chen & Bing Xu

  3. Department of Hematology, Nanfang Hospital. Southern Medical University, Guangzhou, 510515, China

    Pengcheng Shi

  4. Department of Nuclear Medicine, the First Affiliated Hospital of Xiamen University and Institute of Hematology, School of Medicine, Xiamen University, Xiamen, 361003, China

    Hua Wu

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  1. Jie Zha
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Contributions

Conception and design: Jie Zha and Bing Xu. Development of methodology: Jie Zha, Qian Lai, Manman Deng, Pengcheng Shi. Material preparation, data collection and analysis: Jie Zha, Qian Lai, Manman Deng,Pengcheng Shi, Haijun Zhao, Qinwei Chen.Writing, and revision of the manuscript:Jie Zha, Qian Lai and Bing Xu.Writing, and revision of the manuscript: Jie Zha,Hua Wu, Bing Xu. Supplemental experiments: Jie zha. Response to reviewers: Jiezha,Hua Wu and Bing Xu.

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Correspondence to Bing Xu.

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Zha, J., Lai, Q., Deng, M. et al. Disruption of CTCF Boundary at HOXA Locus Promote BET Inhibitors’ Therapeutic Sensitivity in Acute Myeloid Leukemia. Stem Cell Rev and Rep 16, 1280–1291 (2020). https://doi.org/10.1007/s12015-020-10057-y

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