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TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype.
Sallman, David A; McLemore, Amy F; Aldrich, Amy L; Komrokji, Rami S; McGraw, Kathy L; Dhawan, Abhishek; Geyer, Susan; Hou, Hsin-An; Eksioglu, Erika A; Sullivan, Amy; Warren, Sarah; MacBeth, Kyle J; Meggendorfer, Manja; Haferlach, Torsten; Boettcher, Steffen; Ebert, Benjamin L; Al Ali, Najla H; Lancet, Jeffrey E; Cleveland, John L; Padron, Eric; List, Alan F.
Afiliação
  • Sallman DA; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • McLemore AF; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • Aldrich AL; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • Komrokji RS; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • McGraw KL; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • Dhawan A; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • Geyer S; Health Informatics Institute, University of South Florida, Tampa, FL.
  • Hou HA; Division of Hematology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
  • Eksioglu EA; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • Sullivan A; NanoString Technologies, Inc., Seattle, WA.
  • Warren S; NanoString Technologies, Inc., Seattle, WA.
  • MacBeth KJ; Celgene Corporation, San Francisco, CA.
  • Meggendorfer M; MLL Munich Leukemia Laboratory, Munich, Germany.
  • Haferlach T; MLL Munich Leukemia Laboratory, Munich, Germany.
  • Boettcher S; Department of Medical Oncology and Hematology, University Hospital and University of Zurich, Zurich, Switzerland.
  • Ebert BL; Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, MA.
  • Al Ali NH; Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; and.
  • Lancet JE; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • Cleveland JL; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • Padron E; Department of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
  • List AF; Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL.
Blood ; 136(24): 2812-2823, 2020 12 10.
Article em En | MEDLINE | ID: mdl-32730593
ABSTRACT
Somatic gene mutations are key determinants of outcome in patients with myelodysplastic syndromes (MDS) and secondary AML (sAML). In particular, patients with TP53 mutations represent a distinct molecular cohort with uniformly poor prognosis. The precise pathogenetic mechanisms underlying these inferior outcomes have not been delineated. In this study, we characterized the immunological features of the malignant clone and alterations in the immune microenvironment in patients with TP53-mutant and wild-type MDS or sAML. Notably, PDL1 expression is significantly increased in hematopoietic stem cells of patients with TP53 mutations, which is associated with MYC upregulation and marked downregulation of MYC's negative regulator miR-34a, a p53 transcription target. Notably, patients with TP53 mutations display significantly reduced numbers of bone marrow-infiltrating OX40+ cytotoxic T cells and helper T cells, as well as decreased ICOS+ and 4-1BB+ natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-1-) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow-infiltrating ICOShigh/PD-1- Treg cells is a highly significant independent predictor of overall survival. We conclude that the microenvironment of TP53 mutant MDS and sAML has an immune-privileged, evasive phenotype that may be a primary driver of poor outcomes and submit that immunomodulatory therapeutic strategies may offer a benefit for this molecularly defined subpopulation.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndromes Mielodisplásicas / Leucemia Mieloide Aguda / Proteína Supressora de Tumor p53 / Linfócitos T Reguladores / Células Supressoras Mieloides / Mutação Tipo de estudo: Prognostic_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Blood Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Síndromes Mielodisplásicas / Leucemia Mieloide Aguda / Proteína Supressora de Tumor p53 / Linfócitos T Reguladores / Células Supressoras Mieloides / Mutação Tipo de estudo: Prognostic_studies Limite: Adult / Aged / Aged80 / Female / Humans / Male / Middle aged Idioma: En Revista: Blood Ano de publicação: 2020 Tipo de documento: Article