{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"volume":["119(3)"],"submitter":["Benoit A"],"funding":["Cancer Research Society","Leukemia and Lymphoma Society of Canada / Societe de Leucemie &amp; Lymphome Du Canada","Canadian Cancer Society","Michael Smith Health Research BC","Fonds de Recherche du Québec - Santé","Cole Foundation"],"pubmed_abstract":["Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6<sup>D419</sup> mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6<sup>D419</sup> mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6<sup>D419</sup> mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6<sup>D419N</sup> was retained in the nucleus longer than phospho-STAT6<sup>WT</sup> following IL-4 stimulation, and STAT6<sup>D419N</sup> recognized a more restricted DNA-consensus sequence than STAT6<sup>WT.</sup> Upon IL-4 induction, STAT6<sup>D419N</sup> expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STAT<sup>WT</sup>. The most significantly expressed genes induced by STAT6<sup>D419N</sup> 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<sup>+</sup> rrDLBCL cells had a greater proportion of infiltrating CD4<sup>+</sup> T-cells than phospho-STAT6<sup>-</sup> tumors. Our findings suggest that STAT6<sup>D419</sup> mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment."],"journal":["International journal of hematology"],"pagination":["275-290"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10920476"],"repository":["biostudies-literature"],"pubmed_title":["STAT6 mutations enriched at diffuse large B-cell lymphoma relapse reshape the tumor microenvironment."],"pmcid":["PMC10920476"],"pubmed_authors":["Santiago R","Coyle KM","Assouline S","Abraham MJ","Del Rincon SV","Mann KK","Kim J","Hilton LK","Morin RD","Bakadlag R","Makhani K","Li S","Tu R","Dmitrienko S","Benoit A","Johnson NA","Klein KO","Guilbert C","Subramaniam N","Estrada-Tejedor R","Salaciak M"],"additional_accession":[]},"is_claimable":false,"name":"STAT6 mutations enriched at diffuse large B-cell lymphoma relapse reshape the tumor microenvironment.","description":"Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6<sup>D419</sup> mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6<sup>D419</sup> mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6<sup>D419</sup> mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6<sup>D419N</sup> was retained in the nucleus longer than phospho-STAT6<sup>WT</sup> following IL-4 stimulation, and STAT6<sup>D419N</sup> recognized a more restricted DNA-consensus sequence than STAT6<sup>WT.</sup> Upon IL-4 induction, STAT6<sup>D419N</sup> expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STAT<sup>WT</sup>. The most significantly expressed genes induced by STAT6<sup>D419N</sup> 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<sup>+</sup> rrDLBCL cells had a greater proportion of infiltrating CD4<sup>+</sup> T-cells than phospho-STAT6<sup>-</sup> tumors. Our findings suggest that STAT6<sup>D419</sup> mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-06-02T20:57:10.428Z","creation":"2025-06-25T03:06:18.759Z"},"accession":"S-EPMC10920476","cross_references":{"pubmed":["38285120"],"doi":["10.1007/s12185-023-03692-x"]}}