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Cited by 88Cancer-related Molecular PathwaysAcute Myeloid Leukemia ResearchProtein Tyrosine Phosphatases

A Gain-of-Function p53-Mutant Oncogene Promotes Cell Fate Plasticity and Myeloid Leukemia through the Pluripotency Factor FOXH1

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Loizou, Evangelia, Banito, Ana, Livshits, Geulah, Ho, Yu-Jui, Koche, Richard P., Sánchez-Rivera, Francisco J., Mayle, Allison, Chen, Chi-Chao +5 more·2019·Cancer Discovery
DOI 10.1158/2159-8290.cd-18-1391PMC PMC6606372

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Abstract

Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype AML (CK-AML). Here, we identify a gain-of-function (GOF) Trp53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The Trp53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPC) even prior to their transformation. We identify FOXH1 as a critical mediator of mutant p53 function that binds to and regulates stem cell–associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 GOF in cancer. Significance: Our study demonstrates how a GOF p53 mutant can hijack an embryonic transcription factor to promote aberrant self-renewal. In this context, mutant Trp53 functions as an oncogene to both initiate and sustain myeloid leukemia and suggests a potential convergent activity of mutant Trp53 across cancer types. This article is highlighted in the In This Issue feature, p. 813

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  • Loss of the TP53-WT allele confers an additional fitness advantage to TP53-sAML LSCs.

    “Despite the known dominant negative and/or gain of function effect of certain TP53 mutations28,42, loss of the TP53-WT allele, a genetic event associated with a particularly dismal prognosis2, confers an additional fitness advantage to TP53-sAML LSCs.”

    From Single-cell multi-omics identifies chronic inflammation as a driver of TP53-mutant leukemic evolution (2023) · cites this paper as [42]

    The Results section (“p53R172H enhances self-renewal in hematopoietic cells in vitro and in vivo”; page unavailable) reports enhanced self-renewal in mutant mouse hematopoietic cells only after loss of the remaining wild-type p53 allele, along with a competitive advantage in transplantation. It does not directly establish that loss of the TP53-WT allele gives human TP53-sAML leukemia stem cells an additional fitness advantage. (LLM, conf=0.84)

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Authors
Loizou, E., Banito, A., Livshits, G., Ho, Y.-J., Koche, R. P., Sánchez-Rivera, F. J., Mayle, A., Chen, C.-C., Kinalis, S., Bagger, F. O., Kastenhuber, E. R., Durham, B. H., & Lowe, S. W.
Affiliations
  • Memorial Sloan Kettering Cancer Center (US)
  • 1Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York.
  • University of Copenhagen (DK)
Corresponding author
Lowe, Scott W.
ORCID
Venue
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Published
2019-07-01
Volume
9
Issue
7
Pages
962-979
ISSN
  • 2159-8274 (ISSN-L)
  • 2159-8290
DOI
10.1158/2159-8290.cd-18-1391
PMC
PMC6606372
OpenAlex
W2944511181
Cited by
88
References
7
Citations by year
2026: 7 · 2025: 12 · 2024: 12 · 2023: 15 · 2022: 12 · 2021: 9 · 2020: 15 · 2019: 6
FWCI
4.38
Type
journal article
Language
en
Open access
Locations
  • Cancer Discovery (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (R01 CA190261, P30 CA008748)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
Keywords
FOXH1, myeloid leukemia, cell fate plasticity, hematopoietic stem and progenitor cells, self-renewal, pluripotency, oncogenes, disease maintenance
MeSH terms
Cell Plasticity, Gain of Function Mutation, Animals, Humans, Mice, Transgenic, Neoplastic Stem Cells, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Mice, SCID, Mice, Inbred NOD, Mice, Knockout, Gene Expression Profiling, Xenograft Model Antitumor Assays, Pluripotent Stem Cells, Cell Line, Tumor, Mice, Forkhead Transcription Factors

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