AML with pDC expansion, or pDC-AML, is associated with RUNX1 mutations in the vast majority of cases (∼70%). Xiao et al demonstrate that blasts from pDC-AML that harbor RUNX1 mutations may acquire an interferon-driven pDC transcriptional program, thereby leading to increased pDCs. pDCs are known to express/overexpress CD123, or IL3Rα, which can uniquely be targeted by CD123-directed therapy. Tagraxofusp (SL-401, DT-IL3) is the first approved agent targeting CD123 (BPDCN, age ≥2 years, December 2018), opening up the possibility of novel avenues for therapeutic investigation. Figure by N. Pemmaraju.