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Cited by 196Acute Myeloid Leukemia ResearchCancer Immunotherapy and BiomarkersCancer-related Molecular Pathways

The DOI matches its Crossref record; 52 of the 53 references it cites were found in a registry or an index.

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

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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.·2020·Blood
DOI 10.1182/blood.2020006158PMC PMC7731792
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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.

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  1. Sallman, 2019, The First-in-Class Anti-CD47 Antibody Magrolimab (5F9) in Combination with Azacitidine Is Effective in MDS and AML Patients: Ongoing Phase 1b Results [abstract], Blood, 134

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Metadata

Authors
Sallman, D. A., McLemore, A. F., Aldrich, A. L., Komrokji, R. S., McGraw, K. L., Dhawan, A., Geyer, S., Hou, H.-A., 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.
Affiliations
  • Moffitt Cancer Center (US)
  • University of South Florida (US)
  • National Taiwan University Hospital (TW)
  • Nanostring Technologies (United States) (US)
  • Celgene Corporation, San Francisco, CA;
  • Munich Leukemia Laboratory (Germany) (DE)
  • University of Zurich (CH)
  • Broad Institute (US)
  • Department of Malignant Hematology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL;
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2020-12-10
Volume
136
Issue
24
Pages
2812-2823
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2020006158
PMC
PMC7731792
OpenAlex
W3046762554
Cited by
196
References
53
Citations by year
2026: 26 · 2025: 31 · 2024: 30 · 2023: 38 · 2022: 39 · 2021: 30 · 2020: 2
FWCI
17.21
Type
journal article
Language
en
Open access
Locations
  • Blood (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R35CA253125, P30CA076292)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
TP53 mutation, myelodysplastic syndrome, secondary acute myeloid leukemia, tumor immune microenvironment, immunosuppression, PD-L1 expression, hematopoietic stem cells, miR-34a, regulatory T cells, myeloid-derived suppressor cells, cytotoxic T lymphocytes, natural killer cells, ICOS, 4-1BB, prognostic factors, overall survival, immunomodulatory therapy
MeSH terms
Myeloid-Derived Suppressor Cells, Adult, Aged, Aged, 80 and over, Female, Humans, Immunosuppression Therapy, Male, Middle Aged, Mutation, Myelodysplastic Syndromes, RNA, Neoplasm, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, MicroRNAs, T-Lymphocytes, Regulatory

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