Preexisting TP53 mutation in therapy-related acute myeloid leukemia.
Ontology highlight
ABSTRACT:
SUBMITTER: Schulz E
PROVIDER: S-EPMC4317506 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:The p53 tumor suppressor directs the cellular response to many mechanistically distinct DNA-damaging agents and is selected against during the pathogenesis of therapy-related acute myeloid leukemia (t-AML). We hypothesized that constitutional genetic variation in the p53 pathway would affect t-AML risk. Therefore, we tested associations between patients with t-AML (n = 171) and 2 common functional p53-pathway variants, the MDM2 SNP309 and the TP53 codon 72 polymorphism. Although neither polymorphism alone influenced the risk of t-AML, an interactive effect was detected such that MDM2 TT TP53 Arg/Arg double homozygotes, and individuals carrying both a MDM2 G allele and a TP53 Pro allele, were at increased risk of t-AML (P value for interaction is .009). This interactive effect was observed in patients previously treated with chemotherapy but not in patients treated with radiotherapy, and in patients with loss of chromosomes 5 and/or 7, acquired abnormalities associated with prior exposure to alkylator chemotherapy. In addition, there was a trend toward shorter latency to t-AML in MDM2 GG versus TT homozygotes in females but not in males, and in younger but not older patients. These data indicate that the MDM2 and TP53 variants interact to modulate responses to genotoxic therapy and are determinants of risk for t-AML.
| S-EPMC2481552 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a devastating disease with an incidence that progressively increases with advancing age. Currently, only ∼40% of younger and 10% of older adults are long-term survivors. If untreated, the overall prognosis of AML remains dismal. Initiation of therapy at diagnosis is usually urgent. Barriers to successful therapy for AML are the attendant toxicities directly related to chemotherapy or those associated with inevitable aplasia. Organ dysfunction often further complicates such toxicities and may even be prohibitive. There are few guidelines to manage such patients and the fear of crossing the medico-legal abyss may dominate. Such clinical scenarios provide particular challenges and require experience for optimal management. Herein, we discuss select examples of common pretreatment comorbidities, including cardiomyopathy, ischemic heart disease; chronic renal failure, with and without dialysis; hepatitis and cirrhosis; chronic pulmonary insufficiency; and cerebral vascular disease. These comorbidities usually render patients ineligible for clinical trials and enormous uncertainty regarding management reigns, often to the point of withholding definitive therapy. The scenarios described herein emphasize that with appropriate subspecialty support, many AML patients with comorbidities can undergo therapy with curative intent and achieve successful long-term outcome.
| S-EPMC5524532 | biostudies-other
Project description:Mutation of the tumor suppressor gene, TP53, is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it is the most commonly mutated gene in cancer, its occurrence is observed in only 5-10% of de novo AML, and in 30% of therapy related AML (t-AML). TP53 mutation serves as a prognostic marker of poor response to standard-of-care chemotherapy, particularly in t-AML and AML with complex cytogenetics. In light of a poor response to traditional chemotherapy and only a modest improvement in outcome with hypomethylation-based interventions, allogenic stem cell transplant is routinely recommended in these cases, albeit with a response that is often short lived. Despite being frequently mutated across the cancer spectrum, progress and enthusiasm for the development of p53 targeted therapeutic interventions is lacking and to date there is no approved drug that mitigates the effects of TP53 mutation. There is a mounting body of evidence indicating that p53 mutants differ in functionality and form from typical AML cases and subsequently display inconsistent responses to therapy at the cellular level. Understanding this pathobiological activity is imperative to the development of effective therapeutic strategies. This review aims to provide a comprehensive understanding of the effects of TP53 on the hematopoietic system, to describe its varying degree of functionality in tumor suppression, and to illustrate the need for the adoption of personalized therapeutic strategies to target distinct classes of the p53 mutation in AML management.
| S-EPMC8509740 | biostudies-literature
Project description:BackgroundSecondary tumors, including therapy-related acute myeloid leukemia (t-AML), represent one of the most undesirable side effects of chemotherapy, which arise several years after primary cancer treatment. This review aims to analyze the current data on molecular pathogenesis of t-AML revealing potential criteria for predicting predisposition to the disease. Another objective is to analyze the information on promising approaches for t-AML prevention.MethodsWe analyzed studies regarding t-AML and possible approaches for cancer prevention of drug-induced tumors. Publications in the databases, such as SciVerse Scopus (948), PubMed (1837) and Web of Science (935) were used. Among 92 the most important publications cited in the review, 79 were published during the last decade.ResultsThe review provides the information concerning t-AML pathogenesis, molecular markers of primary cancer patients with high risk of t-AML. The role of the bone marrow niche in clonal hematopoiesis and t-AML pathogenesis is discussed. Current approaches for t-AML prevention both at the stage of therapy and at the latent period are described. Inhibition effects of polyphenols on cell proliferation and on the appearance of hemopoetic clones of indeterminate potential are proposed for t-AML prevention.ConclusionThe problem of the t-AML, a cancer induced by genotoxic chemotherapeutic drugs, is considered from the point of view of the fundamental mechanisms of chemical carcinogenesis, highlighting initiation and promotion stages. It enables to reveal the possible markers for the group of patients with high risk for t-AML and to demonstrate perspectives for the use of plant polyphenols for t-AML prevention.
| S-EPMC7811901 | biostudies-literature
Project description:Vosaroxin is a quinolone compound that intercalates DNA and induces TP53-independent apoptosis, demonstrating activity against acute myeloid leukemia (AML) in Phase I-III trials. Here, we examine vosaroxin's mechanism of action and pharmacology, and we review its use in AML to date, focusing on details of individual clinical trials. Most recently, when combined with cytarabine in a randomized Phase III trial (VALOR), vosaroxin improved outcomes versus cytarabine alone for relapsed/refractory AML in patients older than 60 years and for patients in early relapse. We consider its continued role in the context of a multifaceted strategy against AML, including its current use in clinical trials. Prospective use will define its role in the evolving landscape of AML therapy.
| S-EPMC5144553 | biostudies-literature
Project description:Late relapse, defined as relapse arising after at least 5 years of remission, is rare and occurs in 1-3% of patients with acute myeloid leukemia (AML). The underlying mechanisms of late relapse remain poorly understood. We identified patients with AML who achieved remission with standard induction chemotherapy and relapsed after at least five years of remission (n?=?15). Whole exome sequencing was performed in available bone marrow samples obtained at diagnosis (n?=?10), remission (n?=?6), and first relapse (n?=?10). A total of 41 driver mutations were identified, of which 11 were primary tumor-specific, 17 relapse-specific, and 13 shared (detected both in primary and relapsed tumor samples). We demonstrated that 12 of 13 shared mutations were in epigenetic modifier and spliceosome genes. Longitudinal genomic characterization revealed that in eight of 10 patients the founder leukemic clone persisted after chemotherapy and established the basis of relapse years later. Understanding the mechanisms of such quiescence in leukemic cells may help designing future strategies aimed at increasing remission duration in patients with AML.
| S-EPMC6335405 | biostudies-other
Project description:TP53 mutations (TP53mut) in AML patients associate with poor prognosis that may affect therapy and outcome. In addition to TP53 mut patients, TCGA AML patient sequencing data show that there are around 3% of patients have detectable low-frequency TP53mut reads. Importantly, these patients showed worse outcome as compared with the TP53 wild type (TP53wt) patients. We have studied the effect of low-frequency TP53mut in two AML cell lines, OCI-AML2 and MV4-11. Both cells have low-frequency single hotspot TP53mut. Interestingly, the resistant cells derived from both lines have homogeneous TP53mut. TP53mut clones isolated from the parental cells also show increased chemoresistance potential and have higher population of leukemia stem cell (LSC) maker positive cells, a characteristic of chemoresistant cells. When mixed with TP53wt cells, the TP53mut cells show survival advantage suggesting its potential to develop chemoresistance. We previously showed that histone deacetylase inhibitor Romidepsin can re-sensitize chemoresistant cells by eradicating LSC marker positive cells. Here we further show that Romidepsin can reactivate p53 targeted genes which are dysregulated in TP53mut cells and preferentially targets TP53mut subpopulation. Therefore, our study shows that low-frequency TP53mut is linked to chemoresistance and sheds light on therapeutic strategies for treatments on chemoresistance.
| S-EPMC7597970 | biostudies-literature
Project description:Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15-4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06-3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making.
| S-EPMC7139772 | biostudies-literature
Project description:BACKGROUND:Mutations in the tumor protein 53 (TP53) gene predict a poor prognosis in patients with acute myeloid leukemia (AML). METHODS:Peripheral blood or bone marrow samples from 293 patients with newly diagnosed AML were analyzed with targeted, amplicon-based, next-generation sequencing-based mutation analysis. RESULTS:TP53 mutations were identified in 53 patients (18%; 45 were missense mutations). In 13 of the 53 patients, the most common pattern of amino acid substitution was a substitution of arginine to histidine on different codons. The clinical characteristics, pattern of mutations, response to different therapies, and outcomes of patients with AML-TP53-mutated (n = 53) versus wild-type TP53 (n = 240) were compared. TP53 mutations were significantly more likely in patients who had a complex karyotype; abnormalities of chromosome 5, 7, and 17; and therapy-related AML. Patients who had TP53-mutated AML had significantly lower incidence of mutations in Fms-like tyrosine kinase 3 (FLT3), rat sarcoma (RAS), and nucleophosmin (NPM1) and higher incidence of coexisting MPL mutations compared with those who had wild type TP53. The distribution of TP53 mutations was equal for both age groups (ages <60 years vs ?60 years). TP53-mutated AML was associated with a lower complete remission rate (41% vs 57%; P = .04), a significantly inferior complete remission duration (at 2 years: 30% vs 55%; P = .001), and overall survival (at 2 years: 9% vs 24%; P ? .0001) irrespective of age or the type of treatment received (high-intensity vs low-intensity chemotherapy). CONCLUSIONS:The type of treatment received did not improve outcomes in younger or older patients with TP53-mutated AML. These data suggest that novel therapies are needed to improve the outcome of patients with AML who have TP53 mutations. Cancer 2016;122:3484-3491. © 2016 American Cancer Society.
| S-EPMC5269552 | biostudies-literature
Project description:BACKGROUND:The molecular determinants of clinical responses to decitabine therapy in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) are unclear. METHODS:We enrolled 84 adult patients with AML or MDS in a single-institution trial of decitabine to identify somatic mutations and their relationships to clinical responses. Decitabine was administered at a dose of 20 mg per square meter of body-surface area per day for 10 consecutive days in monthly cycles. We performed enhanced exome or gene-panel sequencing in 67 of these patients and serial sequencing at multiple time points to evaluate patterns of mutation clearance in 54 patients. An extension cohort included 32 additional patients who received decitabine in different protocols. RESULTS:Of the 116 patients, 53 (46%) had bone marrow blast clearance (<5% blasts). Response rates were higher among patients with an unfavorable-risk cytogenetic profile than among patients with an intermediate-risk or favorable-risk cytogenetic profile (29 of 43 patients [67%] vs. 24 of 71 patients [34%], P<0.001) and among patients with TP53 mutations than among patients with wild-type TP53 (21 of 21 [100%] vs. 32 of 78 [41%], P<0.001). Previous studies have consistently shown that patients with an unfavorable-risk cytogenetic profile and TP53 mutations who receive conventional chemotherapy have poor outcomes. However, in this study of 10-day courses of decitabine, neither of these risk factors was associated with a lower rate of overall survival than the rate of survival among study patients with intermediate-risk cytogenetic profiles. CONCLUSIONS:Patients with AML and MDS who had cytogenetic abnormalities associated with unfavorable risk, TP53 mutations, or both had favorable clinical responses and robust (but incomplete) mutation clearance after receiving serial 10-day courses of decitabine. Although these responses were not durable, they resulted in rates of overall survival that were similar to those among patients with AML who had an intermediate-risk cytogenetic profile and who also received serial 10-day courses of decitabine. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT01687400 .).
| S-EPMC5217532 | biostudies-literature