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

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 Nakagata, Atsushi Iwama, Kazuma Ohyashiki, Motomi Osato () and Goro Sashida ()
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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
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
Kazuma Ohyashiki: Tokyo Medical University
Motomi Osato: National University of Singapore
Goro Sashida: Kumamoto University

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09710-z

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