CTCF boundary remodels chromatin domain and drives aberrant HOX gene transcription in acute myeloid leukemia

Huacheng Luo, Fei Wang, Jie Zha, Haoli Li, Bowen Yan, Qinghua Du, Feng-Chun Yang, Amin Sobh, Christopher Vulpe, Leylah Drusbosky, Christopher Cogle, Iouri Chepelev, Bing Xu, Stephen D. Nimer, Jonathan Licht, Yi Qiu, Baoan Chen, Mingjiang Xu, Suming Huang

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

HOX gene dysregulation is a common feature of acute myeloid leukemia (AML). The molecular mechanisms underlying aberrant HOX gene expression and associated AML pathogenesis remain unclear. The nuclear protein CCCTC-binding factor (CTCF), when bound to insulator sequences, constrains temporal HOX gene-expression patterns within confined chromatin domains for normal development. Here, we used targeted pooled CRISPR-Cas9–knockout library screening to interrogate the function of CTCF boundaries in the HOX gene loci. We discovered that the CTCF binding site located between HOXA7 and HOXA9 genes (CBS7/9) is critical for establishing and maintaining aberrant HOXA9-HOXA13 gene expression in AML. Disruption of the CBS7/9 boundary resulted in spreading of repressive H3K27me3 into the posterior active HOXA chromatin domain that subsequently impaired enhancer/promoter chromatin accessibility and disrupted ectopic long-range interactions among the posterior HOXA genes. Consistent with the role of the CBS7/9 boundary in HOXA locus chromatin organization, attenuation of the CBS7/9 boundary function reduced posterior HOXA gene expression and altered myeloid-specific transcriptome profiles important for pathogenesis of myeloid malignancies. Furthermore, heterozygous deletion of the CBS7/9 chromatin boundary in the HOXA locus reduced human leukemic blast burden and enhanced survival of transplanted AML cell xenograft and patient-derived xenograft mouse models. Thus, the CTCF boundary constrains the normal gene-expression program, as well as plays a role in maintaining the oncogenic transcription program for leukemic transformation. The CTCF boundaries may serve as novel therapeutic targets for the treatment of myeloid malignancies.

Original languageEnglish (US)
Pages (from-to)837-848
Number of pages12
JournalBlood
Volume132
Issue number8
DOIs
StatePublished - Aug 23 2018

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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