Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-09710-z
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Funding
- Takeda Science Foundation
- Uehara Memorial Foundation
- Japanese Society of Hematology
- Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan [16KT0113, 18H02842, 15H04312, 16H06276, 18KT0026, 18K16090, S1511011]
- NCIS Centre Grant Seed Funding Program, Singapore Ministry of Education's AcRF Tier 3 grant [MOE2014-T3-1-006]
- Grants-in-Aid for Scientific Research [16KT0113, 18H02842, 15H04312, 18K16090, 18KT0026] Funding Source: KAKEN
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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.
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