Model of mutated STAT6 (STAT6mut)–mediated pathogenesis in FL. Left panel: FL with wild-type STAT6. FL is characterized by increased numbers of TFH cells, which are the main source of IL-4 production that initiates the cascade of IL-4–STAT6 pathway with activation of STAT6 and induction of STAT6-dependent genes including FCER2 (CD23), CCL17, and CCL22. In some t(14;18)-positive FL cases this might induce the expression of CD23 in the absence of STAT6 mutation. Right panel: FL with activating mutations of STAT6. STAT6 mutations amplify IL-4–induced STAT6-dependent gene activation via an intracellular self-reinforcing regulatory microcircuit that involves aberrantly increased PARP14 levels.52 The increased expression of cytokines CCL17 and CCL22 contribute to re-educate the TME, with further recruitment of IL-4–producing TFH cells. STAT6mut in FL cells cooccurred either with CREBBP mutations and/or TNFRSF14 mutations.32,33,51,CREBBP mutations favor immune evasion and precludes apoptosis by inhibiting the acetylation of CREBBP target genes, BCL6 and TP53.53,54 TNFRSF14 mutations help to re-educate the TME and enhance lymphoma cell survival by disrupting the BTLA–TNFRSF14 pathway.23 Figure created with BioRender.com.
