The two-hit model of leukemogenesis hypothesizes that many cases of AML are the result of the cooperation of two types of mutations: mutations that result in unhindered cell proliferation (class I mutations such as FMS-like tyrosine kinase 3 (FLT3), NRAS, c-KIT) and mutations that result in the arrest of normal myeloid differentiation (class II mutations such as RUNX1-RUNX1T1, CEBPA, TP53).11 Although this two-hit model is a simplification of the biology of AML, it serves as a useful conceptual framework. This evidence concerns the gene RUNX1T1 and acute myeloid leukemia.