Abstract
Leukemia is an evolutionary disease and evolves by the accrual of mutations within a clone. Those mutations that are systematically found in all the patients affected by a certain leukemia are called "drivers" as they are necessary to drive the development of leukemia. Those ones that accumulate over time but are different from patient to patient and, therefore, are not essential for leukemia development are called "passengers." The first studies highlighting a potential cooperating role of phosphatidylinositol 3-kinase (PI3K)/RAS pathway mutations in the phenotype of KMT2A-rearranged leukemia was published 20 years ago. The recent development in more sensitive sequencing technologies has contributed to clarify the contribution of these mutations to the evolution of KMT2A-rearranged leukemia and suggested that these mutations might confer clonal fitness and enhance the evolvability of KMT2A-leukemic cells. This is of particular interest since this pathway can be targeted offering potential novel therapeutic strategies to KMT2A-leukemic patients. This review summarizes the recent progress on our understanding of the role of PI3K/RAS pathway mutations in initiation, maintenance, and relapse of KMT2A-rearranged leukemia.