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Cited by 112Acute Myeloid Leukemia ResearchCancer Genomics and DiagnosticsCancer-related Molecular Pathways

TP53 copy number and protein expression inform mutation status across risk categories in acute myeloid leukemia

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Tashakori, Mehrnoosh, Kadia, Tapan, Loghavi, Sanam, Daver, Naval, Kanagal-Shamanna, Rashmi, Pierce, Sherry, Sui, Dawen, Wei, Peng +10 more·2022·Blood
DOI 10.1182/blood.2021013983PMC PMC9346958
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Abstract

Mutant TP53 is an adverse risk factor in acute myeloid leukemia (AML), but large-scale integrated genomic-proteomic analyses of TP53 alterations in patients with AML remain limited. We analyzed TP53 mutational status, copy number (CN), and protein expression data in AML (N = 528) and provide a compilation of mutation sites and types across disease subgroups among treated and untreated patients. Our analysis shows differential hotspots in subsets of AML and uncovers novel pathogenic variants involving TP53 splice sites. In addition, we identified TP53 CN loss in 70.2% of TP53-mutated AML cases, which have more deleterious TP53 mutations, as well as copy neutral loss of heterozygosity in 5/32 (15.6%) AML patients who had intact TP53 CN. Importantly, we demonstrate that mutant p53 protein expression patterns by immunohistochemistry evaluated using digital image-assisted analysis provide a robust readout that integrates TP53 mutation and allelic states in patients with AML. Expression of p53 by immunohistochemistry informed mutation status irrespective of TP53 CN status. Genomic analysis of comutations in TP53-mutant AML shows a muted landscape encompassing primarily mutations in genes involved in epigenetic regulation (DNMT3A and TET2), RAS/MAPK signaling (NF1, KRAS/NRAS, PTPN11), and RNA splicing (SRSF2). In summary, our data provide a rationale to refine risk stratification of patients with AML on the basis of integrated molecular and protein-level TP53 analyses.

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  • There is a strong interplay between VAF, allelic state, and cytogenetic complexity predicting outcomes in mTP53 MDS/AML.

    “there is a very strong interplay between VAF, allelic state, and cytogenetic complexity strongly predicting outcomes in this molecular subset”

    From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [10]

    The Results section’s outcome analysis reports that TP53 VAF, number of TP53 mutations, and cytogenetic risk independently correlated with overall survival in frontline TP53-mutated AML; TP53 copy-number loss was associated with worse survival among patients with one TP53 mutation. It does not establish a strong three-way interplay among VAF, allelic state, and cytogenetic complexity, and its outcome analysis concerns AML rather than MDS/AML broadly (page not available in our copy). (LLM, conf=0.86)

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  • A recent study identified 92% of TP53 mutant MDS/AML patients to represent a poor risk population.

    “with a recent study identifying 92% of TP53 mutant MDS/AML patients to represent a poor risk population.”

    From Long‐term follow‐up and combined Phase 2 results of eprenetapopt and azacitidine in patients with <i>TP53</i> mutant MDS/AML (2025) · cites this paper as [10]

    The Introduction describes TP53-mutated AML as an adverse-risk category. But the study group was patients with AML, not a combined MDS/AML population, and the 92.5% reported in Methods refers to myelodysplasia-related cytogenetics among patients with AML-MRC—not the proportion of TP53-mutant patients at poor risk. (LLM, conf=0.87)

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Authors
Tashakori, M., Kadia, T., Loghavi, S., Daver, N., Kanagal-Shamanna, R., Pierce, S., Sui, D., Wei, P., Khodakarami, F., Tang, Z., Routbort, M., Bivins, C. A., Jabbour, E. J., Medeiros, L. J., Bhalla, K., Kantarjian, H. M., Ravandi, F., & Khoury, J. D.
Affiliations
  • University of Minnesota (US)
  • 3Department of Leukemia, and
  • The University of Texas MD Anderson Cancer Center (US)
  • 1Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX;
  • 5Cyclica Inc, Toronto, ON, Canada
Corresponding author
Khoury, Joseph D.
ORCID
Venue
Blood
Publisher
American Society of Hematology
Published
2022-07-07
Volume
140
Issue
1
Pages
58-72
ISSN
  • 0006-4971 (ISSN-L)
  • 1528-0020
DOI
10.1182/blood.2021013983
PMC
PMC9346958
OpenAlex
W4226526247
Cited by
111
References
36
Citations by year
2026: 17 · 2025: 24 · 2024: 31 · 2023: 27 · 2022: 12
FWCI
17.28
Type
journal article
Language
en
Open access
Licence
Locations
  • Blood (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Digital Commons-TMC (Texas Medical Center) (submittedVersion)
Topics
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
acute myeloid leukemia, TP53 mutation, p53 expression, immunohistochemistry, copy-neutral loss of heterozygosity, co-occurring mutations, DNMT3A, TET2, RAS/MAPK pathway, SRSF2, risk stratification
MeSH terms
Humans, Mutation, Prognosis, Leukemia, Myeloid, Acute, Tumor Suppressor Protein p53, Proteomics, Epigenesis, Genetic, DNA Copy Number Variations

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