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

Sho Kubota,Henry Yang,Akinori Kanai,Kar Tong Tan,Eisaku Iwanaga,Goro Sashida,Kenji Tokunaga,Kazuma Ohyashiki,Norio Asou,Atsushi Iwama,Naomi Nakagata,Motomi Osato,Motohiko Oshima,Takako Yokomizo-Nakano,Yuqi Sun,Tomohiro Umezu,Takahiro Maeda

doi:10.1038/s41467-019-09710-z

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.

Highlights

Sho Kubota 1, Kenji Tokunaga2, Tomohiro Umezu 3, Takako Yokomizo-Nakano1, Yuqi Sun1, Motohiko Oshima4,5, Kar Tong Tan6, Henry Yang6, Akinori Kanai7, Eisaku Iwanaga2, Norio Asou8, Takahiro Maeda9, Naomi Nakagata10, Atsushi Iwama4,5, Kazuma Ohyashiki3, Motomi Osato6,11,12 & Goro Sashida 1
Since the super-enhancer of RUNX2 has been detected in Blastic plasmacytoid dendritic cell neoplasm (BPDCN) cells harboring t(6;8), which involves a region adjacent to MYC12,27, we initially examined the expression levels of RUNX2 and MYC in leukemic cells harboring t(6;8) in patients and the cell line, CAL-1, which has a loss-of-function mutation in TET2 (Supplementary Fig. 1)6
The expression levels of RUNX2 were significantly higher in BPDCN cells than in acute myeloid leukemia (AML) cells and U2OS and Saos2 osteosarcoma cells as Saos2 has higher expression level of RUNX2 than normal counterpart cells and promotes the cell growth28, while the expression levels of RUNX2 were lower in BPDCN cells than in mature plasmacytoid dendritic cells (pDCs) isolated from healthy donors (Fig. 1a)

Summary

Introduction

Sho Kubota 1, Kenji Tokunaga, Tomohiro Umezu 3, 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 Osato6,11,12 & Goro Sashida 1. The pDC-specific RUNX2 super-enhancer is hijacked to activate MYC in addition to RUNX2 expression, thereby promoting the proliferation of BPDCN. These authors contributed : Sho Kubota, Kenji Tokunaga. Super-enhancers are large clusters of enhancers that are densely occupied by transcription factors and mediators, such as BRD4, which drive the transcriptional activation of critical genes that define cell identity through their regulation of differentiation. The inhibition of BRD4 was shown to significantly abrogate the proliferative capacity of BPDCN, at least in part, due to the suppression of TCF4 transcription. The inhibition of BRD4 was shown to significantly abrogate the proliferative capacity of BPDCN, at least in part, due to the suppression of TCF4 transcription12,20 These lineagesurvival transcription factors appear to utilize the activation of super-enhancers from precursors of and/or mature pDCs and confer transformation properties in BPDCN

Methods

Results

Conclusion