A variant in IRF3 impacts on the clinical outcome of AML patients submitted to Allo-SCT

• Published in: Bone marrow transplantation (Basingstoke) Vol. 48; no. 9; pp. 1205 - 1211
• Main Authors: Martín-Antonio, B, Suarez-Lledo, M, Arroyes, M, Fernández-Avilés, F, Martínez, C, Rovira, M, Espigado, I, Gallardo, D, Bosch, A, Buño, I, Martínez-Laperche, C, Jiménez-Velasco, A, de la Cámara, R, Brunet, S, Nieto, J B, Urbano-Ispizua, Á
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.09.2013; Nature Publishing Group
• Subjects: 631/250/1904; 631/250/248; 692/699/249/1529; 692/699/67/1990/283/1897; Adolescent; Adult; Aged; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antigen presentation; Antigens; Biological and medical sciences; Bone marrow; Bone marrow, stem cells transplantation. Graft versus host reaction; Cell Biology; Clinical outcomes; Cytotoxicity; Disease-Free Survival; Gene Expression Regulation, Neoplastic; Genotype; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Leukemia Effect - immunology; Graft-versus-host reaction; Hematologic and hematopoietic diseases; Hematology; Hematopoietic Stem Cell Transplantation - adverse effects; Hematopoietic Stem Cell Transplantation - methods; Histocompatibility antigen HLA; Humans; Immunity, Innate - genetics; Immunity, Innate - immunology; Interferon regulatory factor 3; Interferon Regulatory Factor-3 - genetics; Interferon Regulatory Factor-3 - immunology; Internal Medicine; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - immunology; Leukemia, Myeloid, Acute - surgery; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphocytes; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Natural killer cells; original-article; Patients; Polymorphism, Single Nucleotide; Public Health; Single nucleotide polymorphisms; Stem cell transplantation; Stem Cells; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Transplantation Conditioning - methods; Transplantation, Homologous; Young Adult; γ-Interferon; Spain; GVHD; innate immunity; IFN regulatory factor-3; transplantation; scientific section; Acute myelogenous leukemia; Prognosis; Genetic variability; Stem cell; Hematopoietic cell; Homograft; Natural immunity; Transplantation; Allogeneic hematopoietic stem cell transplantation; Surgery; Graft; Human; Immunopathology; Graft versus host disease; Hematology; Genotype; Malignant hemopathy; Section; Variant; Treatment; Interferon regulatory factor 3; Interferon regulatory factor; Cancer
• DOI: 10.1038/bmt.2013.43
• ISSN: 0268-3369

Allo-SCT has a strong curative potential for AML patients mainly due to a GVL effect. Unfortunately, GvL and GVHD are intimately linked. IFN regulatory factor-3 (IRF3), by modulating innate immune reactions, could impact on the incidence and intensity of GVL and GVHD. We analyzed two gene variants in IRF3 (rs7251 and rs2304205) on the clinical outcome of 249 AML patients submitted to HLA-identical sibling allo-SCT. Patients with a donor carrying the dominant GG gene variant in rs7251 had, as compared with GC and CC variants, a lower acute GVHD (aGVHD) III–IV incidence (4% vs 11% vs 27%; P =0.0078), a higher relapse incidence (49% vs 35% vs 26%; P =0.018), and lower TRM (7% vs 24% vs 18%; P =0.0065). In functional studies, the GG variant was associated with lower production of IFN-γ, decreased lymphocyte proliferation after antigen presentation by DCs, and lower cytotoxic response of mature natural killer cells. Patients carrying the AA dominant variant in rs2304205 had higher relapse incidence (50% vs 39% vs 18%, P =0.0068). The presence of both variants (GG in rs7251 and AA in rs2304205) in donors and patients resulted in a stronger clinical impact.