We propose a convincing model directly linking the leukemia-initiating event (i.e., the t(12;21) ETV6-RUNX1 translocation) with upregulation of RAG1 as well as with a stronger activity of RAG recombinase as observed in ETV6-RUNX1 BCP-ALL leukemogenesis. This evidence concerns the gene RUNX1 and acute lymphoblastic leukemia.