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Cited by 82Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchProtein Tyrosine Phosphatases

Low-burden TP53 mutations in chronic phase of myeloproliferative neoplasms: association with age, hydroxyurea administration, disease type and JAK2 mutational status

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Kubesova, B, Pavlova, S, Malcikova, J, Kabathova, J, Radova, L, Tom, N, Tichy, B, Plevova, K +12 more·2018·Leukemia
DOI 10.1038/leu.2017.230PMC PMC5808067
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Abstract

The multistep process of TP53 mutation expansion during myeloproliferative neoplasm (MPN) transformation into acute myeloid leukemia (AML) has been documented retrospectively. It is currently unknown how common TP53 mutations with low variant allele frequency (VAF) are, whether they are linked to hydroxyurea (HU) cytoreduction, and what disease progression risk they carry. Using ultra-deep next-generation sequencing, we examined 254 MPN patients treated with HU, interferon alpha-2a or anagrelide and 85 untreated patients. We found TP53 mutations in 50 cases (0.2-16.3% VAF), regardless of disease subtype, driver gene status and cytoreduction. Both therapy and TP53 mutations were strongly associated with older age. Over-time analysis showed that the mutations may be undetectable at diagnosis and slowly increase during disease course. Although three patients with TP53 mutations progressed to TP53-mutated or TP53-wild-type AML, we did not observe a significant age-independent impact on overall survival during the follow-up. Further, we showed that complete p53 inactivation alone led to neither blast transformation nor HU resistance. Altogether, we revealed patient's age as the strongest factor affecting low-burden TP53 mutation incidence in MPN and found no significant age-independent association between TP53 mutations and hydroxyurea. Mutations may persist at low levels for years without an immediate risk of progression.

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  • TP53-mutant subclones are present in 16% of chronic phase MPN (CP-MPN), and in most cases this does not herald the development of TP53-sAML.

    “Notwithstanding the established role of TP53 mutation in MPN transformation, TP53-mutant subclones are also present in 16% of chronic phase MPN (CP-MPN), and in most cases, this does not herald the development of TP53-sAML (ref. 15).”

    From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [15]

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Authors
Kubesova, B., Pavlova, S., Malcikova, J., Kabathova, J., Radova, L., Tom, N., Tichy, B., Plevova, K., Kantorova, B., Fiedorova, K., Slavikova, M., Bystry, V, Kissova, J., Gisslinger, B., Gisslinger, H., Penka, M., Mayer, J., Kralovics, R., Pospisilova, S., & Doubek, M.
Affiliations
  • Central European Institute of Technology – Masaryk University (CZ)
  • Medical University of Vienna (AT)
  • Masaryk University (CZ)
ORCID
Venue
Leukemia
Publisher
Springer Science and Business Media LLC
Published
2017-07-24
Volume
32
Issue
2
Pages
450-461
ISSN
  • 0887-6924 (ISSN-L)
  • 1476-5551
DOI
10.1038/leu.2017.230
PMC
PMC5808067
OpenAlex
W2739409493
Cited by
82
References
6
Citations by year
2026: 7 · 2025: 8 · 2024: 7 · 2023: 8 · 2022: 13 · 2021: 8 · 2020: 13 · 2019: 9 · 2018: 7 · 2017: 2
FWCI
4.87
Type
journal article
Language
en
Open access
Licence
Locations
  • Leukemia (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Technology Agency of the Czech Republic (TACR TE02000058, TE02000058, LM2015064, LQ1601)
  • Ministerstvo Školství, Mládeže a Tělovýchovy (LM2011020, CEITEC2020, LM2015064, TE02000058, LQ1601)
  • Central European Institute of Technology (LQ1601, LM 2011020)
  • Masarykova Univerzita (LQ1601)
  • Lékařská fakulta, Masarykova univerzita
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
TP53 mutation, myeloproliferative neoplasms, chronic phase, variant allele frequency, hydroxyurea, age, JAK2 mutation, acute myeloid leukemia transformation, p53 inactivation, interferon alfa-2a, anagrelide, disease progression, overall survival, hydroxyurea resistance
MeSH terms
Adult, Aged, Aged, 80 and over, Alleles, Female, Gene Frequency, Humans, Hydroxyurea, Male, Middle Aged, Mutation, Myeloproliferative Disorders, Retrospective Studies, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Disease Progression, Janus Kinase 2, Young Adult, High-Throughput Nucleotide Sequencing

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