STAT6 mutations enriched at diffuse large B-cell lymphoma relapse reshape the tumor microenvironment

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.