AFF1 and leukemia: If we sum the frequency of all the mutations reported in the PI3K-RAS pathway in each study, we can clearly observe that in pediatric KMT2A-AFF1 cases the mutation frequency reaches 80% to 90%, at least in the most recent publications where more sensitive sequencing technologies have been applied.32,33 This can lead us to speculate that mutations in the RAS/PI3K pathway could be the second hits for early leukemia onset at least for some patients, as those carrying the translocations KMT2A-AFF1.