TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype

Blood. 2020 Dec 10;136(24):2812-2823. doi: 10.1182/blood.2020006158.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Female
  • Humans
  • Immunosuppression Therapy
  • Leukemia, Myeloid, Acute* / genetics
  • Leukemia, Myeloid, Acute* / immunology
  • Leukemia, Myeloid, Acute* / pathology
  • Male
  • MicroRNAs / genetics
  • MicroRNAs / immunology
  • Middle Aged
  • Mutation*
  • Myelodysplastic Syndromes* / genetics
  • Myelodysplastic Syndromes* / immunology
  • Myelodysplastic Syndromes* / pathology
  • Myeloid-Derived Suppressor Cells / immunology*
  • Myeloid-Derived Suppressor Cells / pathology
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / immunology
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Tumor Suppressor Protein p53* / immunology


  • MIRN34 microRNA, human
  • MicroRNAs
  • RNA, Neoplasm
  • TP53 protein, human
  • Tumor Suppressor Protein p53