MAPK pathway mutations in PI3K inhibitor resistance to CLL. (A) Heatmap showing the distribution of mutations in selected genes based on response status. Previously described CLL drivers and PI3K pathway mutations from responders (left) and nonresponders (right) are plotted on the basis of their CCF values. In the heatmap, color gradation from blue (low) to red (high) indicates the range of CCF values. The 7 genes exclusively mutated in nonresponders are highlighted in the black box. (B) Clonal evolution of the mutations in MAP2K1 (in patient JB-0055) and PLEKHA1 (in patient JB-0061), derived by using the ABSOLUTE and PhylogicNDT tools. Each colored line represents a CCF distribution of a given gene cluster at different time points (T-01, T-02, and T-03 for JB-0055 and T-01 and T-02 for JB-0061). (C) Gene set enrichment analysis comparing the RNA-seq results from CLL samples before and after treatment with a PI3K inhibitor, from 2 primary nonresponders and 3 progressors after initial response. P < .001, q = 0.03. Idela, idelalisib.