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Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia

Author

Listed:
  • Moritz Binder

    (Mayo Clinic
    Mayo Clinic)

  • Ryan M. Carr

    (Mayo Clinic)

  • Terra L. Lasho

    (Mayo Clinic)

  • Christy M. Finke

    (Mayo Clinic)

  • Abhishek A. Mangaonkar

    (Mayo Clinic)

  • Christopher L. Pin

    (University of Western Ontario)

  • Kurt R. Berger

    (University of Western Ontario)

  • Amelia Mazzone

    (Mayo Clinic
    Mayo Clinic)

  • Sandeep Potluri

    (University of Birmingham)

  • Tamas Ordog

    (Mayo Clinic)

  • Keith D. Robertson

    (Mayo Clinic)

  • David L. Marks

    (Mayo Clinic)

  • Martin E. Fernandez-Zapico

    (Mayo Clinic)

  • Alexandre Gaspar-Maia

    (Mayo Clinic
    Mayo Clinic)

  • Mrinal M. Patnaik

    (Mayo Clinic
    Mayo Clinic)

Abstract

Myeloid neoplasms are clonal hematopoietic stem cell disorders driven by the sequential acquisition of recurrent genetic lesions. Truncating mutations in the chromatin remodeler ASXL1 (ASXL1MT) are associated with a high-risk disease phenotype with increased proliferation, epigenetic therapeutic resistance, and poor survival outcomes. We performed a multi-omics interrogation to define gene expression and chromatin remodeling associated with ASXL1MT in chronic myelomonocytic leukemia (CMML). ASXL1MT are associated with a loss of repressive histone methylation and increase in permissive histone methylation and acetylation in promoter regions. ASXL1MT are further associated with de novo accessibility of distal enhancers binding ETS transcription factors, targeting important leukemogenic driver genes. Chromatin remodeling of promoters and enhancers is strongly associated with gene expression and heterogenous among overexpressed genes. These results provide a comprehensive map of the transcriptome and chromatin landscape of ASXL1MT CMML, forming an important framework for the development of novel therapeutic strategies targeting oncogenic cis interactions.

Suggested Citation

  • Moritz Binder & Ryan M. Carr & Terra L. Lasho & Christy M. Finke & Abhishek A. Mangaonkar & Christopher L. Pin & Kurt R. Berger & Amelia Mazzone & Sandeep Potluri & Tamas Ordog & Keith D. Robertson & , 2022. "Oncogenic gene expression and epigenetic remodeling of cis-regulatory elements in ASXL1-mutant chronic myelomonocytic leukemia," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29142-6
    DOI: 10.1038/s41467-022-29142-6
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    References listed on IDEAS

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