| description |
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an aggressive subtype of acute myeloid 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 the major tumor suppressors of TET2 and TP53; however, the molecular mechanisms underlying the pathogenesis of BPDCN have not yet been elucidated. Since translocation (6;8)(p21;q24), which is a rare, but specific anomaly for BPDCN, involves regions adjacent to RUNX2 and MYC, we demonstrated that a pDC-specific super-enhancer of RUNX2 was associated with the MYC promoter due to t(6;8). Since RUNX2 is critical for the differentiation of pDCs accompanied by the emergence of the lineage-specific super-enhancer of RUNX2, RUNX2 ensured the expression of pDC-signature genes in leukemic cells, but also conferred survival and proliferative properties in BPDCN cells. Furthermore, the inhibition of BRD4 and genetic deletion of the mutant-allele super-enhancer of RUNX2 markedly impaired the proliferative capacity of BPDCN cells following the significant reduction in MYC expression, indicating that the translocation juxtaposed the pDC-specific RUNX2 super-enhancer with MYC and aberrantly activated MYC expression, thereby promoting the development of BPDCN. We also demonstrated that the transduction of RUNX2 and MYC was sufficient to initiate the transformation of BPDCN in mice lacking Tet2 and Tp53, providing a new model that accurately recapitulates the aggressive human disease and gives an insight into the molecular mechanisms underlying the pathogenesis of BPDCN. Our results also support a new rationale for combined applications of BRD4 inhibitors with agents targeting pDC-signature genes driven by RUNX2 in patients. |