The advent of the Next-Generation Sequencing technologies has enabled the detection of rare subclonal mutations.49,50 Taking advantage of this technology Andersson et al performed a detailed genome and transcriptome wide analysis on diagnostic and matched relapse samples of infant KMT2A-rearranged ALL and found that although the genome of these leukemias are “silent,” with only 1.3 somatic mutations per clone, the most mutated pathway was the RAS/PI3K pathway.31 This has been confirmed by other studies32,33,35,43 (Fig. 2 and Supplemental Table 1, Supplemental Digital Content). Here, PIK3CA is linked to acute lymphoblastic leukemia.