We herein demonstrate that the pDC-specific RUNX2 super-enhancer is hijacked to activate expression of MYC via t(6;8) in BPDCN cells, and unveil the molecular mechanisms underlying the pathogenesis of BPDCN, which originates from a precursor of pDCs by utilizing a mouse model. Here, RUNX2 is linked to CD4+/CD56+ hematodermic neoplasm.