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Cited by 152Acute Myeloid Leukemia ResearchGenomics and Chromatin DynamicsChromatin Remodeling and Cancer

HOXA9 Reprograms the Enhancer Landscape to Promote Leukemogenesis

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Sun, Yuqing, Zhou, Bo, Mao, Fengbiao, Xu, Jing, Miao, Hongzhi, Zou, Zhenhua, Phuc Khoa, Le Tran, Jang, Younghoon +9 more·2018·Cancer Cell
DOI 10.1016/j.ccell.2018.08.018PMC PMC6179449
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Abstract

Aberrant expression of HOXA9 is a prominent feature of acute leukemia driven by diverse oncogenes. Here we show that HOXA9 overexpression in myeloid and B progenitor cells leads to significant enhancer reorganizations with prominent emergence of leukemia-specific de novo enhancers. Alterations in the enhancer landscape lead to activation of an ectopic embryonic gene program. We show that HOXA9 functions as a pioneer factor at de novo enhancers and recruits CEBPα and the MLL3/MLL4 complex. Genetic deletion of MLL3/MLL4 blocks histone H3K4 methylation at de novo enhancers and inhibits HOXA9/MEIS1-mediated leukemogenesis in vivo. These results suggest that therapeutic targeting of HOXA9-dependent enhancer reorganization can be an effective therapeutic strategy in acute leukemia with HOXA9 overexpression.

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  • Some studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers.

    “While some studies show that signalling-dependent and cell type-specific TFs are capable of recruiting MLL4 to establish H3K4me1 at enhancers44–47, whether HNF4A has this function is not known.”

    From HNF4A guides the MLL4 complex to establish and maintain H3K4me1 at gene regulatory elements (2024) · cites this paper as [47]

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Authors
Sun, Y., Zhou, B., Mao, F., Xu, J., Miao, H., Zou, Z., Phuc Khoa, L. T., Jang, Y., Cai, S., Witkin, M., Koche, R., Ge, K., Dressler, G. R., Levine, R. L., Armstrong, S. A., Dou, Y., & Hess, J. L.
Affiliations
  • University of Michigan (US)
  • National Institutes of Health (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • Boston Children's Hospital (US)
  • Indiana University Indianapolis (US)
Corresponding author
  • Dou, Yali
  • Hess, Jay L.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2018-10
Volume
34
Issue
4
Pages
643-658.e5
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccell.2018.08.018
PMC
PMC6179449
OpenAlex
W2893367264
Cited by
152
References
5
Citations by year
2026: 10 · 2025: 18 · 2024: 13 · 2023: 17 · 2022: 18 · 2021: 21 · 2020: 44 · 2019: 10 · 2018: 1
FWCI
15.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion)
  • Purdue University Indianapolis (Indiana University) (submittedVersion)
Funders
  • AACR
  • Leukemia and Lymphoma Society Scholar
  • Leukemia and Lymphoma Society Specialized Center of Excellence
  • NIH (CA151425)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
HOXA9, acute leukemia, leukemogenesis, pioneer factors, C/EBPα, histone H3 lysine 4 methylation, MEIS1, myeloid progenitor cells
MeSH terms
Animals, Cell Transformation, Neoplastic, Enhancer Elements, Genetic, Humans, Methylation, Promoter Regions, Genetic, Leukemia, Myeloid, Acute, Homeodomain Proteins

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