Prognostic and therapeutic impacts of mutant TP53 variant allelic frequency in newly diagnosed acute myeloid leukemia

Blood Advances, Journal Year: 2020, Volume and Issue: 4(22), P. 5681 - 5689

Published: Nov. 19, 2020

TP53 mutations are associated with poor outcomes in acute myeloid leukemia (AML). The prognostic impact of mutant (TP53mut) variant allelic frequency (VAF) is not well established, nor how this information might guide optimal frontline therapy. We retrospectively analyzed 202 patients newly diagnosed TP53-mutated AML who underwent first-line therapy either a cytarabine- or hypomethylating agent (HMA)-based regimen. By multivariate analysis, TP53mut VAF >40% was independently significantly higher cumulative incidence relapse (P = .003) and worse relapse-free survival .001) overall (OS; P .003). on clinical driven by treated cytarabine-based regimen (median OS, 4.7 vs 7.3 months for ≤40%; .006), whereas did affect OS HMA. addition venetoclax to HMA compared without venetoclax, both the entire population stratified VAF. Among ≤40%, superior those higher-dose cytarabine, similarly regardless best long-term were observed 1 mutation ≤40% received (2-year 38% 6% all others; < .001). In summary, provides important that may be considered when selecting AML.

Language: Английский

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Heterogeneity of TP53 Mutations and P53 Protein Residual Function in Cancer: Does It Matter?

Frontiers in Oncology, Journal Year: 2020, Volume and Issue: 10

Published: Oct. 28, 2020

The human TP53 locus, located on the short arm of chromosome 17, encodes a tumour suppressor protein which functions as tetrameric transcription factor capable regulating expression plethora target genes involved in cell cycle arrest, apoptosis, DNA repair, autophagy, and metabolism regulation. is most commonly mutated gene cancer cells germ-line mutations are responsible development cancer-prone Li-Fraumeni syndrome. When mutated, generally presents missense mutations, can be distributed throughout coding sequence, although they found frequently central binding domain protein. may represent an important prognostic predictive marker cancers. presence mutation does not necessarily implies complete P53 inactivation; fact, mutant proteins functionally heterogeneous classified loss function, partial temperature sensitive, with altered specificity, wild type-like, super-transactivating, dominant or gain function. Different models have been used to explore these never-ending facets generating abundant experimental data their functional impact. Here, we briefly review studies different effects possible implications for clinical outcome. focus shall Chronic Lymphocytic Leukemia (CLL), also has generated considerable discussion role therapy decisions.

Language: Английский

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Outcome of aggressive B-cell lymphoma with TP53 alterations administered with CAR T-cell cocktail alone or in combination with ASCT

Signal Transduction and Targeted Therapy, Journal Year: 2022, Volume and Issue: 7(1)

Published: April 11, 2022

Abstract TP53 gene alteration confers inferior prognosis in refractory/relapse aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL). From September 2016 to 2020, 257 r/r B-NHL patients were assessed for eligibility two trials our center, assessing anti-CD19 and anti-CD22 chimeric antigen receptor (CAR19/22) T-cell cocktail treatment alone or combination with autologous stem cell transplantation (ASCT). alterations screened 123 enrolled confirmed 60. CAR19/22 administration resulted best objective (ORR) complete (CRR) response rate of 87.1% 45.2% alterations, respectively. Following a median follow-up 16.7 months, progression-free survival (PFS) was 14.8 24-month overall (OS) estimated at 56.3%. Comparable ORR, PFS, OS determined individuals without different risk levels based on functional stratification alterations. ASCT higher CRR, OS, but reduced occurrence severe CRS this patient population, even showing stable progressive disease before transplantation. The ORR CRR 92.9% 82.1%, 21.2 PFS rates 77.5% 89.3%, In multivariable analysis, strategy predicted improved OS. conclusion, therapy is efficacious Combining CAR-T further improves long-term outcome these patients.

Language: Английский

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TP53 in MDS and AML: Biological and clinical advances

Cancer Letters, Journal Year: 2024, Volume and Issue: 588, P. 216767 - 216767

Published: Feb. 27, 2024

Language: Английский

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TP53‐Mutated Myeloid Neoplasms: 2024 Update on Diagnosis, Risk‐Stratification, and Management

American Journal of Hematology, Journal Year: 2025, Volume and Issue: unknown

Published: March 11, 2025

ABSTRACT Alterations in the tumor suppressor gene TP53 are common human cancers and associated with an aggressive nature. Approximately 8%–12% of myelodysplastic syndrome (MDS) acute myeloid leukemia (AML) harbor mutations ( mut ) present immense challenges due to inherent chemoresistance poor outcomes. As more older individuals those secondary/therapy‐related neoplasms (MN), their incidence is expected increase aging population rising proportion cancer survivors. Treatments used for other MN—intensive chemotherapy, hypomethylating agents, BCL‐2 inhibitor venetoclax—do not improve survival MN patients meaningfully. Additionally, further development many promising agents has been discontinued, highlighting challenges. Widespread acknowledgment these problems led recognition as a distinct entity 5th edition World Health Organization International Consensus Classifications. However, critical discrepancies between two classifications may lead under‐ or overestimation prognostic risk. Here, we review recent advances biology, diagnosis, treatment MN. The positioned at intersection age, hereditary predisposition, anti‐cancer therapies. Precursor clones can be detected years prior eventual leukemic transformation—raising possibility early intervention. We discuss classification systems bearing on timely effective management. provide novel evidence areas discrepancies. Finally, current therapeutic landscape obvious limitations currently

Language: Английский

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TP53 Mutations in Acute Myeloid Leukemia: Still a Daunting Challenge?

Frontiers in Oncology, Journal Year: 2021, Volume and Issue: 10

Published: Feb. 8, 2021

TP53 is a key tumor suppressor gene with protean functions associated preservation of genomic balance, including regulation cellular senescence, apoptotic pathways, metabolism functions, and DNA repair. The vast majority de novo acute myeloid leukemia (AML) present unaltered alleles. However, mutations are frequently detected in AML related to an increased instability, such as therapy‐related (t-AML) or myelodysplasia-related changes. Of note, complex cytogenetic abnormalities, advanced age, chemoresistance, poor outcomes. Recent breakthroughs research the development targeted drugs directed at specific have led explosion novel treatments different mechanisms. optimal treatment strategy for patients harboring remains critical area unmet need. In this review, we focus on incidence clinical significance t-AML. influence these alterations response outcomes well current future therapeutic perspectives hardly treatable setting discussed.

Language: Английский

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Outcomes in patients with newly diagnosed TP53‐mutated acute myeloid leukemia with or without venetoclax‐based therapy

Cancer, Journal Year: 2021, Volume and Issue: 127(19), P. 3541 - 3551

Published: June 28, 2021

Venetoclax (VEN) in combination with a hypomethylating agent (HMA) has become the standard of care for patients aged >75 years and those not eligible intensive chemotherapy who have newly diagnosed acute myeloid leukemia (AML). The benefit VEN-based therapy AML mutations TP53 gene (TP53mut ) over is undefined.In this single-institutional, retrospective analysis, authors assessed clinical outcomes 238 TP53mut compared characteristics, response to different therapies, received (n = 58) non-VEN-based 180) regimens.Patients regimens were older (aged >65 years: 81% vs 65%; P .02) had higher rates (complete remission, 43% 32%; .06) than regimens. Compared regimens, no difference overall survival (median, 6.6 5.7 months; .4) or relapse-free 4.7 3.5 .43) was observed regardless age intensity treatment.The addition VEN treatment did improve younger AML. These data highlight need novel therapies beyond outcome

Language: Английский

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TP53 in Acute Myeloid Leukemia: Molecular Aspects and Patterns of Mutation

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(19), P. 10782 - 10782

Published: Oct. 5, 2021

Mutation of the tumor suppressor gene, TP53, is associated with abysmal survival outcomes in acute myeloid leukemia (AML). Although it most commonly mutated gene cancer, its occurrence observed only 5–10% de novo AML, and 30% therapy related AML (t-AML). TP53 mutation serves as a prognostic marker poor response to standard-of-care chemotherapy, particularly t-AML complex cytogenetics. In light traditional chemotherapy modest improvement outcome hypomethylation-based interventions, allogenic stem cell transplant routinely recommended these cases, albeit that often short lived. Despite being frequently across cancer spectrum, progress enthusiasm for development p53 targeted therapeutic interventions lacking date there no approved drug mitigates effects mutation. There mounting body evidence indicating mutants differ functionality form from typical cases subsequently display inconsistent responses at cellular level. Understanding this pathobiological activity imperative effective strategies. This review aims provide comprehensive understanding on hematopoietic system, describe varying degree suppression, illustrate need adoption personalized strategies target distinct classes management.

Language: Английский

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Combined inhibition of BCL-2 and MCL-1 overcomes BAX deficiency-mediated resistance of TP53-mutant acute myeloid leukemia to individual BH3 mimetics

Blood Cancer Journal, Journal Year: 2023, Volume and Issue: 13(1)

Published: April 24, 2023

Abstract TP53 -mutant acute myeloid leukemia (AML) respond poorly to currently available treatments, including venetoclax-based drug combinations and pose a major therapeutic challenge. Analyses of RNA sequencing reverse phase protein array datasets revealed significantly lower BAX levels in compared TP53– wild-type (WT) AML, finding confirmed isogenic CRISPR-generated -knockout AML. The response either BCL-2 (venetoclax) or MCL-1 (AMG176) inhibition was BAX-dependent much reduced -WT cells, while the combination two BH3 mimetics effectively activated BAX, circumventing survival mechanisms cells treated with mimetic, synergistically induced cell death AML stem/progenitor cells. mimetic–driven stress patterns after dual were largely independent status affected by apoptosis induction. Co-targeting, but not individual targeting mice xenografted -R248W Molm13 suppressed both growth prolonged survival. Our results demonstrate that co-targeting overcomes deficiency-mediated resistance thus shifting fate from -deficient This concept warrants clinical evaluation.

Language: Английский

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TP53 Mutation in Acute Myeloid Leukemia: An Old Foe Revisited

Cancers, Journal Year: 2023, Volume and Issue: 15(19), P. 4816 - 4816

Published: Sept. 30, 2023

TP53 is the most commonly mutated gene in human cancers and was first tumor suppressor to be discovered history of medical science. Mutations occur at various genetic locations exhibit significant heterogeneity among patients. occurring primarily within DNA-binding domain result loss p53 protein's capability. However, a complex phenotypic landscape often combines gain-of-function, dominant negative, or altered specificity features. This complexity poses challenge developing an effective treatment strategy, which eradicates TP53-mutated cancer clones. review summarizes current understanding mutations AML their implications. mutation AML: In patients with acute myeloid leukemia (AML), six hotspot (R175H, G245S, R248Q/W, R249S, R273H/S, R282W) are common. frequently associated karyotype subgroups therapy-related secondary AML. The presence considered as poor prognostic factor. even classified distinct subgroup by itself, exhibits significantly terms co-mutation expression profiles compared wildtype (WT)-TP53 AML.To better predict prognosis different mutations, several predictive scoring systems have been proposed based on screening experiments, assess aggressiveness cells. Among those systems, relative fitness score (RFS) could applied overall survival (OS) event-free (EFS). standard treatment, includes cytotoxic chemotherapy allogeneic hematopoietic stem cell transplantation, largely ineffective for Consequently, succumb months, despite active anticancer treatment. Decitabine, hypomethylating agent, known relatively Numerous trials ongoing investigate effects novel drugs combined agents, TP53-targeting agents immunologic agents.Developing strategy through innovative multidisciplinary research urgent task. Directly targeting holds promise approach combating AML, recent developments offer hope this field.

Language: Английский

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