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Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6 D419  mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6 D419 mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6 D419 mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6 D419N was retained in the nucleus longer than phospho-STAT6 WT following IL-4 stimulation, and STAT6 D419N recognized a more restricted DNA-consensus sequence than STAT6 WT. Upon IL-4 induction, STAT6 D419N expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STAT WT . The most significantly expressed genes induced by STAT6 D419N were those implicated in survival, proliferation, migration, and chemotaxis, in particular CCL17. This chemokine, also known as TARC, attracts helper T-cells to the tumor microenvironment, especially in Hodgkin's lymphoma. To this end, in DLBCL, phospho-STAT6 + rrDLBCL cells had a greater proportion of infiltrating CD4 + T-cells than phospho-STAT6 - tumors. Our findings suggest that STAT6 D419 mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment., (© 2024. The Author(s).)