Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1236309 | ENA |
REPOSITORIES: ENA
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Project description:AML with complex karyotype (CK-AML) is characterized by a high frequency of TP53 alteration (loss and/or mutation). TP53-altered CK-AML were characterized by a higher degree of genomic complexity (aberrations per case, 14.30 vs. 6.16; P<.0001), and by a higher frequency of specific copy number alterations, such as -5/5q-, -7/7q-, -16/16q-, -18/18q-, +1/+1p, and +11/+11q/amp11q13~25; among CK-AML, TP53-altered more frequently exhibited a monosomal karyotype (MK). Patients with TP53 alterations were older and had significantly lower complete remission rates, inferior event-free, relapse-free, and overall survival. In multivariable analysis for overall survival, TP53 alterations, white blood cell counts, and age were the only significant factors. In conclusion, TP53 is the most frequently known altered gene in CK-AML. TP53 alterations are associated with older age, genomic complexity, specific DNA copy number alterations, MK, and dismal outcome. In multivariable analysis, TP53 alteration is the most important prognostic factor in CK-AML, outweighing all other variables, including the MK category.
2012-08-27 | GSE34542 | GEO
Project description:Mutations in the TP53 tumor suppressor gene are common in many cancer types, including the acute myeloid leukemia (AML) subtype known as complex karyotype (CK) AML. Here, we identify a gain-of-function (GOF) p53 mutation that accelerates CK-AML initiation beyond p53 loss and, surprisingly, is required for disease maintenance. The p53R172H mutation (TP53R175H in humans) exhibits a neomorphic function by promoting aberrant self-renewal in leukemic cells, a phenotype that is present in hematopoietic stem and progenitor cells (HSPCs) even prior to their transformation. We identify the Forkhead box H1 transcription factor (Foxh1) as a critical mediator of mutant p53 function that binds to and regulates stem cell-associated genes and transcriptional programs. Our results identify a context where mutant p53 acts as a bona fide oncogene that contributes to the pathogenesis of CK-AML and suggests a common biological theme for TP53 gain-of-function in cancer.
2019-05-08 | GSE125097 | GEO
Project description:As part of this study, we isolated induced pluripotent stem cells (iPSCs) from a patient with TP53-mutant MDS and identified loss of chromosome 5q as a cooperating genetic event. Using RNA sequencing we found that loss of chromosome 5q dysregulates genes that maintain chromosome stability, predisposing TP53-mutant cells to chromosomal rearrangements and progression to complex karyotype.
2019-04-17 | GSE129851 | GEO
Project description:Recently, the p53-miR-34a network was identified to play an important role in tumorigenesis. As in acute myeloid leukemia with complex karyotype (CK-AML) TP53 alterations are the most common known molecular lesion, we further analyzed the p53-miR-34a axis in CK-AML with known TP53 status. Clinically, low miR-34a expression and TP53 alterations predicted for chemotherapy resistance and inferior outcome. Notably, in TP53unaltered CK-AML high miR-34a expression predicted for inferior overall survival (OS), whereas in TP53biallelic altered CK-AML high miR-34a expression pointed to better OS. To further investigate miR-34a-associated gene expression patterns, we analyzed distinct subgroups defined by TP53 alteration and miR-34a expression status. Exemplary samples from TP53unaltered (n=6) and TP53biallelic altered (n=6) CK-AML characterized by either high (CK+/miR-34ahigh expression, above median miR-34a expression of the entire cohort), or low (CK+/miR-34alow expression, below median miR-34a expression of the entire cohort) miR-34a expression (n=3 in each group), were analyzed. This molecular profiling linked impaired p53 to decreased miR-34a expression but also identified p53-independent miR-34a induction mechanisms, as shown in TP53biallelic altered cell lines treated with 15-deoxy-∆12,14-prostaglandin (PGJ2). An improved understanding of this mechanism might provide novel therapeutic options to restore miR-34a function and thereby induce cell cycle arrest and apoptosis in TP53altered CK-AML. All samples were obtained from untreated patients at the time of diagnosis. Cells used for microarray analysis were collected from the purified fraction of mononuclear cells after Ficoll density centrifugation. Routine diagnostic algorithms, including the characterization of molecular markers are performed.
2012-08-02 | E-GEOD-39730 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) patients carrying complex karyotype or aneuploidies have a very poor prognosis, with a 5-year overall survival lower than 20%. We and others have shown that complex karyotype and aneuploid patients are characterized by high genomic instability, along with defects of DNA damage response genes and, occasionally, by chromothripsis. Chromothripsis frequently occurs in AML (6.6%) and influences patient prognosis and disease biology. Moreover, the homology recombination pathway is frequently deregulated at expression level in AML. We showed that PALB2 is affect by copy-number deletions in AML (5.2%) and it may be a potential biomarker for very-poor prognosis AML.
2021-01-19 | GSE160982 | GEO
Project description:Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) with complex and monosomy karyotype (CK/MK) show high prevalence of TP53 mutations, poor response to induction chemotherapy and adverse patient outcome. These diseases may respond to decitabine but the mechanisms are presently unclear. MDS/AML patients were treated with decitabine for 10 days in a Phase II clinical study. In this study, we collected serial samples from patients before and at completion of decitabine treatment, morphologic remission and relapse. The samples were interrogated with targeted myeloid panel sequencing, nanopore DNA cytosine methylation sequencing and single-cell transcriptomics to investigate potential interactions between leukemic and immune populations. The integrative analysis allowed characterization of shifting dynamics within leukemic and immune cell populations in individual patients. Comparison of these trends between TP53 mutated MDS/AML patients who responded to treatment versus TP53 wildtype patients who were refractory to treatment highlighted the complex interplay of leukemic and immune compartments. Single cell transcriptomic analyses confirmed immune activation in TP53m responders after decitabine treatment. At relapse, leukemic populations showed up-regulation of MYC signaling and heat shock response while T-cells showed exhaustion signature. Our work highlighted the complex interplay between leukemic and immune populations in TP53m patients upon decitabine treatment that might account for clinical responses and subsequent relapses.
2025-02-10 | GSE279925 | GEO
Project description:Acute myeloid leukemia with complex karyotype (CK-AML) is characterized by three or more chromosomal aberrations, and comprises 10–12% of AML patients. It is associated with complex chromosomal rearrangements, intra-tumor heterogeneity, therapy resistance and poor overall survival. We aimed to transcriptionally characterize CK-AML by performing RNA sequencing on blasts from 4 CK-AML patient samples.
2024-09-20 | E-MTAB-14420 | biostudies-arrayexpress
Project description:TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cell therapy might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are unable to control AML cell outgrowth in vitro and in vivo compared to TP53 wildtype cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.
2023-10-31 | GSE246335 | GEO
Project description:TP53 is the most commonly mutated gene in human cancer, typically occurring in association with complex cytogenetics and dismal outcomes. Understanding the genetic and non-genetic determinants of TP53- mutation driven clonal evolution and subsequent transformation is a crucial step towards the design of rational therapeutic strategies. Here, we carry out allelic resolution single-cell multi-omic analysis of haematopoietic stem/progenitor cells (HSPC) from patients with a myeloproliferative neoplasm who transform to TP53- mutant secondary acute myeloid leukaemia (AML), a tractable model of TP53 -mutant cancer evolution.
2023-05-10 | GSE226340 | GEO