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

David A. Sallman, Amy F. McLemore, Amy L. Aldrich, Rami S. Komrokji, Kathy L. McGraw, Abhishek Dhawan, Susan Geyer, Hsin An Hou, Erika A. Eksioglu, Amy Sullivan, Sarah Warren, Kyle J. MacBeth, Manja Meggendorfer, Torsten Haferlach, Steffen Boettcher, Benjamin L. Ebert, Najla H. Al Ali, Jeffrey E. Lancet, John L. Cleveland, Eric PadronAlan F. List

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

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 OX401 cytotoxic T cells and helper T cells, as well as decreased ICOS1 and 4-1BB1 natural killer cells. Further, highly immunosuppressive regulatory T cells (Tregs) (ie, ICOShigh/PD-12) and myeloid-derived suppressor cells (PD-1low) are expanded in cases with TP53 mutations. Finally, a higher proportion of bone marrow–infiltrating ICOShigh/PD-12 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.

Original languageEnglish (US)
Pages (from-to)2812-2823
Number of pages12
JournalBlood
Volume136
Issue number24
DOIs
StatePublished - Dec 10 2020

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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