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TP53 mutations in myelodysplastic syndromes and secondary AML confer an immunosuppressive phenotype
Open accessAbstract
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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“data in TP53 mutant MDS/AML patients with significant upregulation of PDL1 in leukemic stem cells as well as a highly immunosuppressive microenvironment.”
From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with TP53 mutant MDS/AML (2025) · cites this paper as [51]
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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
- 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
- green
- www.ncbi.nlm.nih.gov
- 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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