We note that loss of function mutations that negatively impact HSC engraftment or activity (Pten, Gfi1, Foxo1,3,4, Bmi1, Moz, Mll1) [46], [47], [48], [49], [50], [51], [52], [53], [54] are either uncommon or not observed in AML, perhaps because HSCs that acquire these mutations as a first hit have a competitive disadvantage in the bone marrow or are rapidly lost. The gene discussed is KMT2A; the disease is acute myeloid leukemia.