The significance of these results presented in this manuscript is three‐fold: 1) identifying a novel co‐factor in IGH::DUX4 transcriptional complexes/machinery; 2) highlighting a TCF12‐mediated self‐feedback regulatory mechanism in oncogenic transaction; 3) revealing the structural basis of IGH::DUX4‐TCF12 cooperation that might be a potent target/direction in future drug design against B‐ALL leukaemia. Here, TCF12 is linked to acute lymphoblastic leukemia.