BPDCN MYB Fusions Regulate Cell Cycle Genes, Impair Differentiation and Induce Myeloid-Dendritic Cell Leukemia [HoxCutRun]

MYB fusions are recurrently found in select cancers, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), an acute leukemia with poor prognosis. They are markedly enriched in BPDCN compared to other blood cancers, and in some patients are the only obvious somatic mutation detected. This suggests they may alone be sufficient to drive dendritic cell transformation. MYB fusions are hypothesized to alter the normal transcription factor activity of MYB, but mechanistically how they promote leukemogenesis is poorly understood. Using CUT&RUN chromatin profiling, we found that in BPDCN leukemogenesis, MYB switches from being a regulator of dendritic cell lineage genes to aberrantly regulating G2/M cell cycle control genes. MYB fusions found in BPDCN patients increased the magnitude of DNA binding at these locations, and this was linked to BPDCN-associated gene expression changes. Furthermore, expression of MYB fusions in vivo impaired dendritic cell differentiation and induced transformation to generate a mouse model of myeloid-dendritic acute leukemia. Therapeutically, we present evidence that all-trans retinoic acid (ATRA) may cause loss of MYB protein and cell death in BPDCN. Overall design: Mouse hematopoietic Hoxb8-FL cells were generated as described (Redecke et al Nat Methods 2013). Wild-type MYB (MYBWT), truncated MYB (MYBTR) or MYB-PLEKHO1 (MYBPLE) were then exogenously expressed in Cdkn2a-WT (CWT) or Cdkn2a-KO (CKO) Hoxb8-FL cells. These cells were co-cultured with MS5 stroma (HoxMS5) or transplanted into recipient mice to generate leukemia (HoxLeu).