Mutations of TCR signaling–related genes in nodal lymphomas of TFH origin. The intracellular pathways after TCR ligation and costimulatory activation were reconstructed using the Ingenuity pathway analysis (IPA) tools, the KEGG database, and other references. Four main pathways are individualized, from left to right: (1) PI3K pathway after CD28/TCR-dependent FYN phosphorylation and ultimately resulting in CTNNB1 translocation into the nucleus; (2) NF-κB/NFAT pathway proximally initiated by ITK-dependent PLCG1 activation and resulting in NFAT1, NF-κB, and IRF4 activation; (3) AP-1/MAPK pathway that comprises ITK-dependent GTF2I activation, MALT1-induced JNKs activation, and PLCG1-GRB2/SOS–induced MAPK components activation; and (4) GTPase-dependent pathway, including RHOA, responsible for cytoskeleton remodeling upon costimulatory/TCR activation. The main positive interactions are indicated by solid green arrows, whereas inhibitory effects are indicated in red. The TCR signaling elements are depicted in yellow or red if the coding genes were mutated in <5% or ≥5% cases, respectively. The most frequently mutated genes (PLCG1, CD28, PI3K components, CTNNB1, and GTF2I) were part of costimulatory, NF-κB/NFAT, PI3K, and AP-1/MAPK intracellular signaling pathways. Proteins corresponding to WT genes are indicated in blue, and genes that were not sequenced are in gray. ERK1, ERK2, JNK1, JNK2, and PDK1 are protein names for MAPK1, MAPK3, MAPK8, MAPK9, and PDPK1 genes, respectively.