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STAT6 mutations enriched at diffuse large B-cell lymphoma relapse reshape the tumor microenvironment.
Benoit, Alexandre; Abraham, Madelyn J; Li, Sheena; Kim, John; Estrada-Tejedor, Roger; Bakadlag, Rowa; Subramaniam, Nivetha; Makhani, Kiran; Guilbert, Cynthia; Tu, Raymond; Salaciak, Matthew; Klein, Kathleen Oros; Coyle, Krysta Mila; Hilton, Laura K; Santiago, Raoul; Dmitrienko, Svetlana; Assouline, Sarit; Morin, Ryan D; Del Rincon, Sonia V; Johnson, Nathalie A; Mann, Koren K.
Afiliação
  • Benoit A; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Abraham MJ; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • Li S; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Kim J; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • Estrada-Tejedor R; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Bakadlag R; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Subramaniam N; University of British Columbia, Vancouver, BC, Canada.
  • Makhani K; Organic and Pharmaceutical Chemistry Department, IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain.
  • Guilbert C; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Tu R; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • Salaciak M; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Klein KO; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • Coyle KM; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Hilton LK; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • Santiago R; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Dmitrienko S; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Assouline S; Department of Pharmacology and Therapeutics, McGill University, Montreal, QC, Canada.
  • Morin RD; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Del Rincon SV; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.
  • Johnson NA; Lady Davis Institute, Jewish General Hospital, 3755 Côte Sainte-Catherine Road, Montreal, QC, H3T 1E2, Canada.
  • Mann KK; Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
Int J Hematol ; 119(3): 275-290, 2024 Mar.
Article em En | MEDLINE | ID: mdl-38285120
ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) relapses in approximately 40% of patients following frontline therapy. We reported that STAT6D419 mutations are enriched in relapsed/refractory DLBCL (rrDLBCL) samples, suggesting that JAK/STAT signaling plays a role in therapeutic resistance. We hypothesized that STAT6D419 mutations can improve DLBCL cell survival by reprogramming the microenvironment to sustain STAT6 activation. Thus, we investigated the role of STAT6D419 mutations on DLBCL cell growth and its microenvironment. We found that phospho-STAT6D419N was retained in the nucleus longer than phospho-STAT6WT following IL-4 stimulation, and STAT6D419N recognized a more restricted DNA-consensus sequence than STAT6WT. Upon IL-4 induction, STAT6D419N expression led to a higher magnitude of gene expression changes, but in a more selective list of gene targets compared with STATWT. The most significantly expressed genes induced by STAT6D419N 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 STAT6D419 mutations in DLBCL lead to cell autonomous changes, enhanced signaling, and altered composition of the tumor microenvironment.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma Difuso de Grandes Células B / Microambiente Tumoral Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Linfoma Difuso de Grandes Células B / Microambiente Tumoral Limite: Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article