Acute Myeloid Leukemia and Myelodysplastic Syndromes with TP53 Aberrations — A Distinct Stem Cell Disorder

Clinical Cancer Research, Journal Year: 2020, Volume and Issue: 26(20), P. 5304 - 5309

Published: Aug. 14, 2020

Abstract The tumor suppressor p53 exerts pivotal roles in hematopoietic stem cell (HSC) homeostasis. Mutations of the TP53 gene have recently been described individuals with clonal hematopoiesis conferring substantial risk developing blood cancers. In patients acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), aberrations—mutations, deletions, a combination thereof—are encountered at constant frequency approximately 10%. These aberrations affect HSCs transforming them into preleukemic cells, pinpointing their central role leukemogenesis. AML MDS are characterized by complex chromosomal aberrations. Respective experience dismal long-term outcome following treatment both intensive nonintensive regimens including novel agents like venetoclax combinations or even allogeneic HSC transplantation. However, according to 2016 WHO classification, still regarded as separate disease entities. On basis common biological clinical features, we propose classify single, distinct disorder unique genetic make-up, comparable classification “AML recurrent abnormalities.” This approach will implications for basic translational research endeavors, aid harmonization current strategies, facilitate development master trials targeting deleterious driver event.

Language: Английский

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Nuclear Proteomics of Induced Leukemia Cell Differentiation

Cells, Journal Year: 2022, Volume and Issue: 11(20), P. 3221 - 3221

Published: Oct. 14, 2022

Studies of induced granulocytic differentiation help to reveal molecular mechanisms cell maturation. The nuclear proteome represents a rich source regulatory molecules, including transcription factors (TFs). It is important have an understanding perturbations at the early stages processes. By applying proteomic quantitative profiling using isobaric labeling, we found that contents 214, 319, 376, 426, and 391 proteins were altered 3, 6, 9, 12, 72 h, respectively, compared 0 h in HL-60 fraction under all-trans-retinoid acid (ATRA) treatment. From 1860 identified proteins, 231 annotated as with factor (TF) activity. Six TFs (RREB1, SRCAP, CCDC124, TRIM24, BRD7, BUD31) downregulated three EWSR1, ENO1, FUS upregulated time points (3-12 h) after ATRA Bioinformatic annotation indicates involvement DNA damage recognition RUNX1-triggered pathway, p53-regulation pathway. scheduled multiple reaction monitoring stable isotopically labeled peptide standards (MRM/SIS), persistent increase content following proteins: PRAM1, CEPBP, RBPJ, HIC1 during ATRA-induced differentiation. In case STAT1, CASP3, PARP1, PRKDC transient their was observed Obtained data on composition dynamics could be beneficial for development new treatment approaches leukemias mutated p53 gene.

Language: Английский

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TP53 mutation in newly diagnosed acute myeloid leukemia and myelodysplastic syndrome

Diagnostic Pathology, Journal Year: 2021, Volume and Issue: 16(1)

Published: Oct. 31, 2021

Abstract Objectives TP53 mutation is found frequently in therapy related acute myeloid leukemia (AML)/ myelodysplastic syndrome (MDS), AML and MDS patients with monosomy or complex karyotype. However, the prevalence treatment outcome mutated AML/MDS Asian population are scarce. We therefore conducted this study to analyze outcomes of MDS-EB patients. Methods Patients newly diagnosed were recruited, extraction deoxyribonucleic acid from bone marrow samples done then performing analysis, using MassArray® System (Agena Bioscience, CA, USA). Results A total 132 de novo AML, secondary MDS-EB1, MDS-EB2 T-AML/MDS seen 66, 13, 9, 9 3%, respectively. was 14 (10.6%), T-AML/MDS, 50, 17.6, 9.2 8%, Three had double heterozygous mutation. Mutated significantly detected chromosome. Common R290C, T220C, A249S V31I which reported only Taiwanese Most variant allele frequency (VAF) greater than 40%. year-overall survival (OS) whole 22%, 3y-OS 22 27%, The 1y-OS TP53-mutant shorter that wild-type patients, 14% versus 50%, P = 0.001. In multivariate factors affecting OS mutant ( 0.023, HR 1.20–7.02), whereas, WBC count > 100,000/μL 0.004, 1.32–4.16) karyotype 0.038, 1.07–9.78) associated Discussion study, low but it impact on survival. more frequent

Language: Английский

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Exome Sequencing in BRCA1-2 Candidate Familias: The Contribution of Other Cancer Susceptibility Genes

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 11

Published: May 7, 2021

Hereditary Breast and Ovarian Cancer (HBOC) syndrome is a condition in which the risk of breast ovarian cancer higher than general population. The prevalent pathogenesis attributable to inactivating variants

Language: Английский

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Comparison of acute myeloid leukemia and myelodysplastic syndromes with TP53 aberrations

Annals of Hematology, Journal Year: 2022, Volume and Issue: 101(4), P. 837 - 846

Published: Jan. 26, 2022

TP53 aberrations are found in approximately 10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) considered early driver events affecting stem cells. In this study, we compared features a total 84 these disorders seen at tertiary cancer center. Clinical cytogenetic characteristics as well immunophenotypes immature blast cells were similar between AML MDS patients. Median overall survival (OS) was 226 days (95% confidence interval [CI], 131-300) for the entire cohort an estimated 3-year OS rate 11% CI, 6-22). showed significant difference (median, 345 days; 95% 235-590) 91 64-226) which is likely due to different co-mutational pattern revealed by next-generation sequencing. Transformation aberrant occurred 60.5% cases substantially reduced their probability. Cox regression analysis treatment class variant allele frequency prognostically relevant parameters but not TP53-specific prognostic scores EAp53 RFS. These data emphasize similarities support previous notions that they should be classified treated distinct disorder.

Language: Английский

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