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Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm

Author

Listed:
  • Sho Kubota

    (Kumamoto University)

  • Kenji Tokunaga

    (Kumamoto University)

  • Tomohiro Umezu

    (Tokyo Medical University)

  • Takako Yokomizo-Nakano

    (Kumamoto University)

  • Yuqi Sun

    (Kumamoto University)

  • Motohiko Oshima

    (Chiba University
    The University of Tokyo)

  • Kar Tong Tan

    (National University of Singapore)

  • Henry Yang

    (National University of Singapore)

  • Akinori Kanai

    (Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University)

  • Eisaku Iwanaga

    (Kumamoto University)

  • Norio Asou

    (Saitama Medical University)

  • Takahiro Maeda

    (Nagasaki University, Graduate School of Biomedical Science)

  • Naomi Nakagata

    (Kumamoto University)

  • Atsushi Iwama

    (Chiba University
    The University of Tokyo)

  • Kazuma Ohyashiki

    (Tokyo Medical University)

  • Motomi Osato

    (National University of Singapore
    Kumamoto University
    Kumamoto University)

  • Goro Sashida

    (Kumamoto University)

Abstract

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute leukemia, the cell of origin of which is considered to be precursors of plasmacytoid dendritic cells (pDCs). Since translocation (6;8)(p21;q24) is a recurrent anomaly for BPDCN, we demonstrate that a pDC-specific super-enhancer of RUNX2 is associated with the MYC promoter due to t(6;8). RUNX2 ensures the expression of pDC-signature genes in leukemic cells, but also confers survival and proliferative properties in BPDCN cells. Furthermore, the pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.

Suggested Citation

  • Sho Kubota & Kenji Tokunaga & Tomohiro Umezu & Takako Yokomizo-Nakano & Yuqi Sun & Motohiko Oshima & Kar Tong Tan & Henry Yang & Akinori Kanai & Eisaku Iwanaga & Norio Asou & Takahiro Maeda & Naomi Na, 2019. "Lineage-specific RUNX2 super-enhancer activates MYC and promotes the development of blastic plasmacytoid dendritic cell neoplasm," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09710-z
    DOI: 10.1038/s41467-019-09710-z
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