Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Kevetrin induces apoptosis in TP53 wild-type and mutant acute myeloid leukemia cells

ABSTRACT: Tumor protein p53 is a key regulator of several cellular pathways, including DNA repair, cell cycle and angiogenesis. Kevetrin exhibits p53-dependent as well as independent activity in solid tumors, while its effects on leukemic cells remain unknown. We analyzed the response of acute myeloid leukemia (AML) cell lines (TP53 wild-type: OCI-AML3 and MOLM-13; and TP53-mutant: KASUMI-1 and NOMO-1) to kevetrin at a concentration range of 85-340 μM. Kevetrin induced cell growth arrest and apoptosis in all cell lines and in primary cells, with TP53-mutant models displaying a higher sensitivity and p53 induction. Gene expression profiling revealed a common core transcriptional program altered by drug exposure and the downregulation of glycolysis, DNA repair and unfolded protein response signatures. These findings suggest that kevetrin may be a promising therapeutic option for patients with both wild-type and TP53-mutant AML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137574 | GEO | 2020/09/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

The phosphoproteomic landscape of 16 Acute Myeloid Leukemia (AML) cell lines

Project description:Acute myeloid leukemia (AML) is a clonal hematopoietic malignancy, characterized by expansion of immature leukemic blasts in the bone marrow. In AML, specific tyrosine kinases have been implicated in leukemogenesis, and are associated with poor treatment outcome. However, targeted therapy using kinase inhibitors (KIs) has had limited success, and may be improved by proper patient selection. We performed phosphotyrosine (pY) based, label-free phosphoproteomics to identify hyperphosphorylated, active kinases in AML cell lines as targets and predictive biomarkers to select KIs for treatment. We identified 3605 class I phosphorylation sites in 16 AML cell lines (EOL-1, KG-1a, MM6, KG-1, ME-1, NB-4, Kasumi-3, MV4-11, THP-1, HEL, HL-60, Kasumi-1, Kasumi-6, ML-2, OCI-AML3, MOLM-13) that exhibited large variation in the number and level of phosphopeptides per cell line (241-2764). Ranking analyses successfully pinpointed the hyperactive kinases PDGFRA, FGFR1, KIT, and FLT3 in eight cell lines with a corresponding kinase mutation. Additionally, we identified unexpected drivers in two more cell lines (PDGFRA in Kasumi-3 and FLT3 in MM6) which proved sensitive to specific kinase inhibitors. Six cell lines without a clear receptor tyrosine kinase (RTK) driver showed evidence of MAPK1/3 activation, consistent with the presence of activating RAS mutations. Our data show the potential of pY phosphoproteomics to identify key drivers in AML cells, and the predictive value of the phosphoproteome profiles in TKi selection for targeted treatment.

2019-11-11 | PXD007237 | Pride

Presence of mutant p53 increases stem cell frequency and is associated with reduced binding to classic TP53 binding sites in cell lines and primary AMLs [ChIP-seq]

Project description:With an overall 5%-10% incidence rate in acute myeloid leukemia (AML), the occurrence of TP53 mutations is low compared with that in solid tumors. However, when focusing on high-risk groups including secondary AML (sAML) and therapy-related AMLs, the frequency of mutations reaches up to 35%. Mutations may include loss of heterozygosity (LOH) or deletion of the 17p allele, but are mostly missense substitutions that are located in the DNA-binding domain. Despite elaborate research on the effects of TP53 mutations in solid tumors, in hematological malignancies, the effects of TP53 mutations versus loss of TP53 remain unclear and under debate. Here, we compared the cellular effects of a TP53 mutant and loss of TP53 in human hematopoietic stem and progenitor cells (HSPCs). We found that when expressing TP53 mutant or loss of TP53 using siRNA, CD34+/CD38- cells have a significantly enhanced replating potential, which could not be demonstrated for the CD34+/CD38+ population. Using RNA-sequencing analysis, we found a loss of expression of p53 target genes in cells with TP53 knockdown. In contrast, an increased expression of a large number of genes was observed when expressing TP53 mutant, resulting in an increase in expression of genes involved in megakaryocytic differentiation, plasma membrane binding, and extracellular structure organization. When binding of p53 wild type and p53 mutant was compared in cell lines, we found that mutant p53 binds to a large number of binding sites genomewide, contrary to wild-type p53, for which binding is restricted to genes with a p53 binding motif. These findings were verified in primary AMLs with and without mutated TP53. In conclusion, in our models, we identified overlapping effects of TP53 mutant and loss of TP53 on in vitro stem cell properties but distinct effects on DNA binding and gene expression.

2023-07-26 | GSE238181 | GEO

Presence of mutant p53 increases stem cell frequency and is associated with reduced binding to classic TP53 binding sites in cell lines and primary AMLs [RNA-seq]

2023-07-26 | GSE238180 | GEO

Neural cell adhesion molecule 1 (NCAM1; CD56) promotes leukemogenesis and confers drug resistance in acute myeloid leukemia.

Project description:Neural cell adhesion molecule 1 (NCAM1; also known as CD56) is expressed in up to 20% of acute myeloid leukemia (AML) patients. Expression of NCAM1 is widely used as a marker of minimal residual disease; however, the biological function of this cell surface protein in AML remains elusive. In this study we investigated the impact of aberrant NCAM1 expression on leukemogenesis, drug resistance and its role as a biomarker to guide therapy.Gene expression profiling was performed with RNA-seq in three cell lines (SKM-1, NOMO-1, MOLM-14) after doxycycline-mediated induction of scrambled shRNA or shNCAM1 at timepoint 72 hours.

2019-02-22 | GSE123071 | GEO

Human AML cell lines LC-MS/MS - Performance of Super-SILAC based quantitative proteomics for comparison of different acute myeloid leukemia (AML) cell lines

Project description:As a direct consequence of the high diversity of the aggressive blood cancer acute myeloid leukemia (AML), proteomic samples from patients are strongly heterogeneous, rendering their accurate relative quantification challenging. In the present study, we investigated the benefits of using a super-SILAC mix of AML derived cell lines as internal standard for quantitative shotgun studies. The Molm-13, NB4, MV4-11, THP-1, and OCI-AML3 cell lines were selected for their complementarity with regard to clinical, cytogenetic and molecular risk factors used for prognostication of AML patients. The resulting internal standard presents a high coverage of the AML proteome compared to single cell lines allied with high technical reproducibility, thus enabling its use for AML patient comparison. This was confirmed by comparing the protein regulation between the five cell lines and applying the internal standard to patient material.

2014-07-15 | PXD000441 | Pride

A gain-of-function p53 mutant oncogene promotes cell fate plasticity and myeloid leukemia through the pluripotency factor Foxh1

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

Activating STING1-dependent immune signaling in TP53 mutant and wild-type acute myeloid leukemia

Project description:In the present study we show that in the subset of acute myeloid leukemias (AML) with mutations in TP53, associated with poor prognosis, DNMTis, important drugs for treatment of AML, enable expression of ERVs and IFN and inflammasome signaling in a STING1 dependent manner. We previously reported in solid tumors that PARPis combined with DNMTis induce an IFN/inflammasome response that is dependent on STING1 and is mechanistically linked to generation of a homologous recombination defect (HRD). We now show that STING1 activity is actually increased in TP53 mutant compared with WT TP53 AML. Moreover, in TP53 mutant AML, STING1-dependent IFN/inflammatory signaling is increased by DNMTi treatment, whereas in AMLs with wild-type (WT) TP53, DNMTis alone have no effect. However, while combining DNMTis with PARPIs now increases IFN/inflammatory gene expression in WT TP53 AML cells, signaling induced in TP53 mutant AML is still several-fold higher. Notably, induction of HRD in both TP53 mutant and WT AMLs follows the pattern of STING1-dependent IFN and inflammatory signaling we have observed with drug treatments. These findings increase our understanding of the mechanisms that underlie DNMTi+PARPi treatment, and also DNMTi combinations with immune therapies, and a personalized approach, stratifying by p53 status, for use of such therapies, including potential immune activation of STING1 in AML and other cancers.

2022-03-07 | GSE197405 | GEO

The expression profiles of AML cell lines

Project description:EVI1 is one of the famous poor prognostic markers for a chemotherapy-resistant acute myeloid leukemia (AML). To identify molecular targets on the surface of leukemia cells with EVI1high expression, we compared the gene expression profiles of several AML cell lines by DNA microarray To search for novel molecular targets in refractory myeloid leukemia with high EVI1 expression, we initially analyzed the gene expression profiles of 12 human myeloid cell lines. Four cell lines with chromosome 3q26 abnormalities (UCSD/AML1, HNT-34, Kasumi-3 and MOLM-1) expressed EVI1High, and eight myeloid cell lines without chromosome 3q26 abnormalities (HEL, HL-60, K052, THP-1, FKH-1, K051, NH and OIH-1) expressed low levels of EVI1 (EVI1Low)

2012-01-18 | E-GEOD-35159 | biostudies-arrayexpress

A gain-of-function p53 mutant synergizes with oncogenic Nras to promote acute myeloid leukemia in mice

Project description:We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have extremely poor prognosis, and most of these TP53 mutations are missense mutations. Here, we report that in contrast to mixed AML and T-cell malignancy developed in NrasG12D/+; p53-/- (NP-/-) mice, NrasG12D/+; p53R172H/+ (NPmut) mice rapidly developed an inflammation-associated AML. Under the inflammatory conditions, NPmut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and largely normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that NrasG12D signaling and p53mut synergize to establish an NPmut-AML transcriptome distinct from that of NA-/- cells. The NPmut-AML transcriptome showed GATA2 downregulation and elevated expression of inflammatory genes, including those linked to NFΚB signaling. NFΚB was also upregulated in human NRAS;TP53 AML. Exogenous expression of GATA2 in human NPmut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NPmut AML cells were sensitive to MEK and NFΚB inhibition in vitro. The proteasome inhibitor bortezomib stabilized NFΚB inhibitory protein IΚBɑ mitigated inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NPmut mice. Our study demonstrates that a p53 structural mutant synergizes with NrasG12D to promote AML through mechanisms distinct from p53 loss.

2023-09-25 | GSE243642 | GEO

TP53 loss and TET2 deficiency cooperate to drive lineage-plastic leukemogenesis by transforming progenitors and establishing immune suppressive environment

Project description:Loss-of-function mutations of TET2 and TP53 genes are frequently co-observed in AML patients receiving intensive chemotherapy and represent independent predictors for inferior survival in patients after stem cell transplantation. Here we show that TET2 biallelic loss or haploinsufficiency is observed in >10% AML patients with TP53 mutations and associated with poor outcome. In mice, double deletions of TET2 and P53 leads to development of T-ALL, B-ALL or AML and stimulation of pre-leukemic mice via TLR2-TRAF6-A20 axis skews leukemia development toward AML. scRNA-seq of murine blasts reveals that B cell leukemia differentiation is accompanied by transcriptional changes of ll7r and Myb while AML commitment is associated with dynamic elevation of Klf4 and Flt3. Notably, mice with AML exhibit T cell exhaustion, NK dysfunction, and MDSC-like properties which are similarly observed in AML patients with TP53/TET2 co-mutations. Lastly, we demonstrated that silencing of MEK/ERK, JAK/STAT or TLR-A20 signaling pathways, that are overexpressed in TP53/TET2-mutant AML, restores normal differentiation in vitro and in vivo. Collectively, these findings provide evidence that TP53 deficiency and TET2 loss cooperate to transform hematopoietic progenitors and play a role in AML development and identify novel targets to deliver therapy for this high-risk AML group.

2023-11-13 | GSE217867 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data