Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation
Open accessAbstract
BACKGROUND: Genetic mutations drive the pathogenesis of the myelodysplastic syndrome (MDS) and are closely associated with clinical phenotype. Therefore, genetic mutations may predict clinical outcomes after allogeneic hematopoietic stem-cell transplantation. METHODS: We performed targeted mutational analysis on samples obtained before transplantation from 1514 patients with MDS who were enrolled in the Center for International Blood and Marrow Transplant Research Repository between 2005 and 2014. We evaluated the association of mutations with transplantation outcomes, including overall survival, relapse, and death without relapse. RESULTS: TP53 mutations were present in 19% of the patients and were associated with shorter survival and a shorter time to relapse than was the absence of TP53 mutations, after adjustment for significant clinical variables (P<0.001 for both comparisons). Among patients 40 years of age or older who did not have TP53 mutations, the presence of RAS pathway mutations was associated with shorter survival than was the absence of RAS pathway mutations (P=0.004), owing to a high risk of relapse, and the presence of JAK2 mutations was associated with shorter survival than was the absence of JAK2 mutations (P=0.001), owing to a high risk of death without relapse. The adverse prognostic effect of TP53 mutations was similar in patients who received reduced-intensity conditioning regimens and those who received myeloablative conditioning regimens. By contrast, the adverse effect of RAS pathway mutations on the risk of relapse, as compared with the absence of RAS pathway mutations, was evident only with reduced-intensity conditioning (P<0.001). In young adults, 4% of the patients had compound heterozygous mutations in the Shwachman-Diamond syndrome-associated SBDS gene with concurrent TP53 mutations and a poor prognosis. Mutations in the p53 regulator PPM1D were more common among patients with therapy-related MDS than those with primary MDS (15% vs. 3%, P<0.001). CONCLUSIONS: Genetic profiling revealed that molecular subgroups of patients undergoing allogeneic hematopoietic stem-cell transplantation for MDS may inform prognostic stratification and the selection of conditioning regimen. (Funded by the Edward P. Evans Foundation and others.).
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Many of the most commonly seen mutations in CHIP are also recurrent drivers of AML, myelodysplastic syndrome (MDS), myeloproliferative neoplasms, and certain lymphomas.
“But many of the most commonly seen mutations in CHIP are also recurrent drivers of AML 64, myelodysplastic syndrome (MDS) 65–67, myeloproliferative neoplasms 68, and certain lymphomas 69,70.”
From Clonal hematopoiesis in human aging and disease (2019) · cites this paper as [67]
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- Authors
- Lindsley, R. C., Saber, W., Mar, B. G., Redd, R., Wang, T., Haagenson, M. D., Grauman, P. V., Hu, Z.-H., Spellman, S. R., Lee, S. J., Verneris, M. R., Hsu, K., Fleischhauer, K., Cutler, C., Antin, J. H., Neuberg, D., & Ebert, B. L.
- Affiliations
- Brigham and Women's Hospital (US)
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2017-02-09
- Volume
- 376
- Issue
- 6
- Pages
- 536-547
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- PMC
- PMC5438571
- OpenAlex
- W2587066646
- Cited by
- 776
- References
- 28
- Citations by year
- 2026: 43 · 2025: 59 · 2024: 93 · 2023: 91 · 2022: 80 · 2021: 100 · 2020: 99 · 2019: 85 · 2018: 69 · 2017: 52
- FWCI
- 64.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL082945, U10HL069294)
- National Cancer Institute (K08CA204734, P01CA066996, U24CA076518, P30CA006516)
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK094746, R24DK099808)
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- myelodysplastic syndrome, allogeneic hematopoietic stem cell transplantation, prognostic mutations, TP53 mutation, RAS pathway mutations, JAK2 mutation, PPM1D mutation, therapy-related MDS, relapse, overall survival, reduced-intensity conditioning, myeloablative conditioning, molecular subtypes
- MeSH terms
- Protein Phosphatase 2C, Adolescent, Adult, Child, DNA Mutational Analysis, Humans, Middle Aged, Mutation, Myelodysplastic Syndromes, Prognosis, Proteins, Transplantation, Homologous, Survival Analysis, Genes, p53, Hematopoietic Stem Cell Transplantation, ras Proteins, Transplantation Conditioning, Janus Kinase 2, Young Adult
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