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

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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, Khodakarami, Farnoosh, Tang, Zhenya, Routbort, Mark, Bivins, Carol A., Jabbour, Elias J., Medeiros, L. Jeffrey, Bhalla, Kapil, Kantarjian, Hagop M., Ravandi, Farhad, Khoury, Joseph D.·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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Crossref · 10.1182/blood.2021013983

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Graphical abstract Visual AbstractCC BY-NC-ND · PubMed Central
Figure 1. Lollipop plot illustrating TP53 mutational data in this study group. (A) FL AML (n = 354 patients). (B) FL AML-MRC (n = 196 patients). (C) FL t-AML (n = 80 patients). (D) Salvage and treated-secondary FL (n = 174 patients) (salvage depicted by square: treated-secondary FL depicted by circles). (E) Splice site mutations in all types of AML (n = 26 patients). Note: Circles are colored according to the corresponding mutation type. Missense (red circles) mutations are shown above the gene schematic diagram, and truncating mutations, including nonsense (green circles), frameshift (blue circles), and deletion (aqua circles), are shown below the diagram. Splice site mutations are depicted in purple circles. At a given locus, lollipop height is proportional to the number of times a mutation was observed in study subjects. The structural domains of the gene represented in the figure: TAD, transactivation domain (TAD1: residues 1 to 40, TAD2 41 to 60 residues); PRD, proline-rich domain (61 to 92 residues); DBD, DNA binding domain (94 to 292 residues); HD, hinge domain (293 to 325 residues); OD, oligomerization domain (326 to 353 residues); CTD, C-terminal domain (354 to 393 residues).37
Figure 1. Lollipop plot illustrating TP53 mutational data in this study group. (A) FL AML (n = 354 patients). (B) FL AML-MRC (n = 196 patients). (C) FL t-AML (n = 80 patients). (D) Salvage and treated-secondary FL (n = 174 patients) (salvage depicted by square: treated-secondary FL depicted by circles). (E) Splice site mutations in all types of AML (n = 26 patients). Note: Circles are colored according to the corresponding mutation type. Missense (red circles) mutations are shown above the gene schematic diagram, and truncating mutations, including nonsense (green circles), frameshift (blue circles), and deletion (aqua circles), are shown below the diagram. Splice site mutations are depicted in purple circles. At a given locus, lollipop height is proportional to the number of times a mutation was observed in study subjects. The structural domains of the gene represented in the figure: TAD, transactivation domain (TAD1: residues 1 to 40, TAD2 41 to 60 residues); PRD, proline-rich domain (61 to 92 residues); DBD, DNA binding domain (94 to 292 residues); HD, hinge domain (293 to 325 residues); OD, oligomerization domain (326 to 353 residues); CTD, C-terminal domain (354 to 393 residues).37CC BY-NC-ND · PubMed Central
Figure 2. Correlation of TP53 CN status with TP53 mutation number, type, and VAF. (A) TP53 CN status among patients with AML with one or more TP53 mutations. Bar lengths drawn to scale. (B) TP53 mutation types and variant allelic frequencies within each of the TP53 CN groups. mut, mutation; sp, splice site; fs, frameshift; ns, nonsense; ms, missense.
Figure 2. Correlation of TP53 CN status with TP53 mutation number, type, and VAF. (A) TP53 CN status among patients with AML with one or more TP53 mutations. Bar lengths drawn to scale. (B) TP53 mutation types and variant allelic frequencies within each of the TP53 CN groups. mut, mutation; sp, splice site; fs, frameshift; ns, nonsense; ms, missense.CC BY-NC-ND · PubMed Central
Figure 3. p53 expression patterns by immunohistochemistry as a readout for TP53 alterations. (A) p53 immunohistochemistry showing high-level (24%) mutant protein accumulation in a trephine bone marrow biopsy with AML (×20). (B) Violin plot showing median and quartiles, with smoothed width reflecting frequency distribution of p53 accumulation levels in bone marrow samples with TP53 mutant and wild-type AML. p53 accumulation is measured using digital image analysis-assisted immunohistochemistry; percentage values represent cells with strong (3+) staining intensity. Cases with mutant p53 truncating pattern are excluded. Dashed line intersecting x-axis depicts 7.2% cutoff. (C) p53 immunohistochemistry showing loss of signal (truncated) mutant pattern. Signal in background stromal elements presents internal control (×20). (D) ROC curve demonstrating an AUC of 0.965 (95% CI: 0.939-0.991), indicating a robust predictive ability for p53 immunohistochemistry to distinguish between AML with mutant and wild-type TP53. (E) Estimates of mutant p53 clone size by dominant VAF and protein expression among p53high and (F) p53truncated. (G) Combined aCGH and SNP analysis of the TP53 gene in AML case with intact TP53 CN; right panel shows corresponding p53high expression by immunohistochemistry [A, C, G: 20× magnification, hematoxylin counterstain].
Figure 3. p53 expression patterns by immunohistochemistry as a readout for TP53 alterations. (A) p53 immunohistochemistry showing high-level (24%) mutant protein accumulation in a trephine bone marrow biopsy with AML (×20). (B) Violin plot showing median and quartiles, with smoothed width reflecting frequency distribution of p53 accumulation levels in bone marrow samples with TP53 mutant and wild-type AML. p53 accumulation is measured using digital image analysis-assisted immunohistochemistry; percentage values represent cells with strong (3+) staining intensity. Cases with mutant p53 truncating pattern are excluded. Dashed line intersecting x-axis depicts 7.2% cutoff. (C) p53 immunohistochemistry showing loss of signal (truncated) mutant pattern. Signal in background stromal elements presents internal control (×20). (D) ROC curve demonstrating an AUC of 0.965 (95% CI: 0.939-0.991), indicating a robust predictive ability for p53 immunohistochemistry to distinguish between AML with mutant and wild-type TP53. (E) Estimates of mutant p53 clone size by dominant VAF and protein expression among p53high and (F) p53truncated. (G) Combined aCGH and SNP analysis of the TP53 gene in AML case with intact TP53 CN; right panel shows corresponding p53high expression by immunohistochemistry [A, C, G: 20× magnification, hematoxylin counterstain].CC BY-NC-ND · PubMed Central
Figure 4. Landscape of comutations in TP53-mutant AML. (A) Untreated (FL). (B) Treated-secondary FL and salvage.
Figure 4. Landscape of comutations in TP53-mutant AML. (A) Untreated (FL). (B) Treated-secondary FL and salvage.CC BY-NC-ND · PubMed Central
Figure 5. Univariate analysis of factors associated with survival outcomes among FL patients with AML. (A) OS; (B) LFS. This analysis included patients with at least 1 TP53 mutation, except for p53 IHC.
Figure 5. Univariate analysis of factors associated with survival outcomes among FL patients with AML. (A) OS; (B) LFS. This analysis included patients with at least 1 TP53 mutation, except for p53 IHC.CC BY-NC-ND · PubMed Central
Figure 6. Kaplan-Meier curves showing outcomes of FL patients with AML by genotype/phenotype p53 status. (A) OS by diagnostic category among patients with mutant TP53. (B) OS by TP53 CN status among patients with 1 TP53 mutation. (C) OS comparison of patients with AML by p53 protein expression patterns detected by immunohistochemistry. (D) OS comparison by immunohistochemistry-based p53 protein expression pattern among patients with any TP53 mutation and intact TP53 CN. NOS, not otherwise specified; RGA, recurrent genetic alteration.
Figure 6. Kaplan-Meier curves showing outcomes of FL patients with AML by genotype/phenotype p53 status. (A) OS by diagnostic category among patients with mutant TP53. (B) OS by TP53 CN status among patients with 1 TP53 mutation. (C) OS comparison of patients with AML by p53 protein expression patterns detected by immunohistochemistry. (D) OS comparison by immunohistochemistry-based p53 protein expression pattern among patients with any TP53 mutation and intact TP53 CN. NOS, not otherwise specified; RGA, recurrent genetic alteration.CC BY-NC-ND · PubMed Central

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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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