LINEAGE-SPECIFIC RUNX2 SUPER-ENHANCER ACTIVATES MYC VIA TRANSLOCATION (6;8) AND PROMOTES THE DEVELOPMENT OF BLASTIC PLASMACYTOID DENDRITIC CELL NEOPLASM

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). BPDCN cells show high frequencies of mutations in TET2 and p53; however, the molecular mechanisms underlying the pathogenesis of BPDCN have not yet been elucidated. 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, which is reversed by the deletion of super-enhancer of RUNX2 or the inhibition of BRD4 function. We also demonstrate that the transduction of MYC and RUNX2 is sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53. Since BPDCN cells show lower expression levels of pDCs-signature genes than mature pDCs in patients and mice, we find that macrophage-dendritic cell progenitors, but not mature pDCs, are at least one of the cells of origin of BPDCN by examining the in vivo tumor initiating capacity of those cells. This study provides a model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN.