TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype
Journal
Blood
Journal Volume
136
Journal Issue
24
Pages
2812-2823
Date Issued
2020
Author(s)
Sallman D.A.
McLemore A.F.
Aldrich A.L.
Komrokji R.S.
McGraw K.L.
Dhawan A.
Geyer S.
Eksioglu E.A.
Sullivan A.
Warren S.
MacBeth K.J.
Meggendorfer M.
Haferlach T.
Boettcher S.
Ebert B.L.
Al Ali N.H.
Lancet J.E.
Cleveland J.L.
Padron E.
List A.F.
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. ? 2020 by The American Society of Hematology.
Other Subjects
microRNA; MIRN34 microRNA, human; protein p53; RNA; TP53 protein, human; antineoplastic agent; cytotoxic T lymphocyte antigen 4; DNA methyltransferase 3A; Flt3 ligand; genomic DNA; isocitrate dehydrogenase 1; isocitrate dehydrogenase 2; Janus kinase 2; K ras protein; microRNA 34a; myeloid differentiation factor 88; nucleophosmin; OX40 ligand; programmed death 1 ligand 1; protein p53; protein tyrosine phosphatase SHP 2; transcription factor ETV6; transcription factor EZH2; transcription factor GATA 2; transcription factor RUNX1; acute myeloid leukemia; adult; aged; female; genetics; human; immunology; immunosuppressive treatment; male; middle aged; mutation; myelodysplastic syndrome; myeloid-derived suppressor cell; pathology; regulatory T lymphocyte; very elderly; adaptive immunity; antigen expression; Article; cancer chemotherapy; cancer diagnosis; chronic myelomonocytic leukemia; clinical article; clinical feature; cohort analysis; controlled study; CRISPR-CAS9 system; cytogenetics; cytotoxic T lymphocyte; down regulation; flow cytometry; gene frequency; helper cell; human cell; immunomodulation; International Prognostic Scoring System; missense mutation; myelodysplastic syndrome; natural killer cell; oncogene N ras; overall survival; phenotype; priority journal; protein expression; secondary acute myeloid leukemia; somatic mutation; tumor microenvironment; upregulation; Adult; Aged; Aged, 80 and over; Female; Humans; Immunosuppression; Leukemia, Myeloid, Acute; Male; MicroRNAs; Middle Aged; Mutation; Myelodysplastic Syndromes; Myeloid-Derived Suppressor Cells; RNA, Neoplasm; T-Lymphocytes, Regulatory; Tumor Suppressor Protein p53
Publisher
American Society of Hematology
Type
journal article