Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Distinct biological and transcriptional features of FLT3-ITD variants in vitro and in vivo

ABSTRACT: Treatment of FLT3-ITD mutated AML remains a clinical challenge as this subset of patients show high incidence of relapse, even after allogeneic stem cell transplantation. Recently, we defined a molecular subset of FLT3-ITD mutations, located in the FLT3-tyrosine kinase domain 1 (TKD1). In multivariable analyses, insertion of ITD variants in the beta1-sheet (TKD1) was identified as an unfavorable prognostic factor for achievement of a complete remission relapse-free survival and overall survival independently of other prognostic factors such as allelic ratio. In the presented analysis we characterize ITD variants located in the TKD1. While transforming capacity and activation of downstream signaling nodes appears comparable to ‘classical’ ITD mutations located in the JM-domain, TKD1-ITDs reveal a distinct gene expression profile and confer decreased sensitivity to kinase inhibitor therapy in vitro and in vivo. This knowledge may impact clinical decisions in regard to TKI therapy versus allogeneic stem cell transplantation.

ORGANISM(S): Mus musculus

PROVIDER: GSE56241 | GEO | 2014/12/31

SECONDARY ACCESSION(S): PRJNA242713

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Molecular variability of FLT3/ITD mutants and their impact on the differentiation program of 32D cells

Project description:FLT3 is the most frequently mutated gene in AML â up to 40% of AML harbor an activating mutation within FLT3 gene. Though AML is a relatively rare disease, such a high mutability rate, as observed with FLT3 gene, is striking. To elucidate the molecular background of this phenomenon, we have established nine unique FLT3/ITD - carrying 32D cell lines and a set of controls, and subjected them to whole genome expression analysis and 2DE LC/MS proteomics. Data obtained on this so far largest set of ITD mutants indicates that in comparison to the wild type FLT3 expressing 32D cells and transduction controls, FLT3/ITD positive cells exhibit less mature expression profiles resembling ST-HSC and MkEP/CMP/LMPP progenitors. We hypothesize that FLT3/ITD might contribute not only to the proliferative advantage of FLT3/ITD positive cells, but also to their reprogramming towards less differentiated stages, thus strengthening their malignant properties. This finding might explain the pronounced mutation rate of the aberrantly expressed FLT3 gene in AML, and, also, the inferior prognosis of FLT3/ITD positive AML patients. Moreover, the microarray data has revealed biological differences among individual ITD variants â a finding supporting the recent clinical data on the prognostic impact of the size of individual ITDs. Keywords: genetic modification Nine stable 32D cell lines harboring unique human FLT3/ITD mutants, two parental 32 cell lines, two 32D stable cell lines harboring cloning vector only, and two 32D cell lines stably expressing human wild type FLT3 were subjected to the microarray analysis.

2010-04-08 | E-GEOD-12766 | biostudies-arrayexpress

Molecular variability of FLT3/ITD mutants and their impact on the differentiation program of 32D cells

Project description:FLT3 is the most frequently mutated gene in AML – up to 40% of AML harbor an activating mutation within FLT3 gene. Though AML is a relatively rare disease, such a high mutability rate, as observed with FLT3 gene, is striking. To elucidate the molecular background of this phenomenon, we have established nine unique FLT3/ITD - carrying 32D cell lines and a set of controls, and subjected them to whole genome expression analysis and 2DE LC/MS proteomics. Data obtained on this so far largest set of ITD mutants indicates that in comparison to the wild type FLT3 expressing 32D cells and transduction controls, FLT3/ITD positive cells exhibit less mature expression profiles resembling ST-HSC and MkEP/CMP/LMPP progenitors. We hypothesize that FLT3/ITD might contribute not only to the proliferative advantage of FLT3/ITD positive cells, but also to their reprogramming towards less differentiated stages, thus strengthening their malignant properties. This finding might explain the pronounced mutation rate of the aberrantly expressed FLT3 gene in AML, and, also, the inferior prognosis of FLT3/ITD positive AML patients. Moreover, the microarray data has revealed biological differences among individual ITD variants – a finding supporting the recent clinical data on the prognostic impact of the size of individual ITDs. Keywords: genetic modification

2009-09-12 | GSE12766 | GEO

Gene expression analysis of WT and Flt3-ITD multipotent progenitors

Project description:FLT3-ITDs Introduce a Myeloid Differentiation and Transformation Bias in Lympho-myeloid Multipotent Progenitors WT multipotent progenitors were compared with FLT3-ITD multipotent progenitors

2014-05-16 | E-GEOD-35805 | biostudies-arrayexpress

Sorafenib promotes graft-versus-leukemia activity in mice and humans through IL-15 production in FLT3-ITD mutant leukemia cells

Project description:Patients relapsing with FLT3-ITD mutant acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (allo-HCT) have a one-year-survival below 20%. We observed that sorafenib increased IL-15 production by FLT3-ITD+-leukemia cells, which synergized with the allogeneic CD8+T-cell response, leading to long-term survival in murine and humanized FLT3-ITD+AML models. Using IL-15 deficiency in recipient tissues or leukemia cells, IL-15 production upon sorafenib-treatment could be attributed to leukemia cells. Sorafenib treatment-related IL-15 production caused an increase in CD8+CD107a+IFN-γ+ T-cells with features of longevity (Bcl-2high/reduced PD-1-levels), which eradicated leukemia in secondary recipients. Mechanistically, sorafenib reduced ATF4 expression, thereby blocking negative regulation of IRF7-activation, which enhances IL-15 transcription. Consistent with the mouse data, IL-15 and pIRF7 levels increased in leukemic blasts of FLT3-ITD+AML patients upon sorafenib treatment. Analysis of 130 patients with FLT3-ITD-mutant AML relapsing after allo-HCT showed the highest complete remission-rate and median overall-survival-rate in the sorafenib/donor lymphocyte infusion (DLI) group compared to all other groups (chemotherapy, chemotherapy/DLI, sorafenib alone). Our findings indicate that the synergism of DLI and sorafenib is mediated via reduced ATF4 expression, causing activation of the pIRF7/IL-15-axis in leukemia cells. The sorafenib/DLI strategy therefore has the potential for an immune-mediated cure of FLT3-ITD-mutant AML- relapse, an otherwise fatal complication after allo-HCT.

2017-12-19 | GSE95770 | GEO

High-throughput identification of FLT3 wild-type and mutant kinase substrate preferences and application to design of sensitive in vitro kinase assay substrates

Project description:Abnormalities in the FLT3 signaling pathway play an integral role in AML disease relapse and drug resistance. Developing new and specific FLT3 tyrosine kinase inhibitors for use in combination to induction therapy is an important step to reduce disease relapse and achieve clinical remission. To develop potent FLT3 TKI requires sensitive in vitro assay that depended on efficient FLT3 artificial substrates, which there are none reported for FLT3 WT and kinase variants. The kinase assay linked with phosphoproteomics was applied as a high throughput technique to increase the known FLT3 kinase substrates (WT, ITD and D835Y) that were used to identify the FLT3 kinase variant’s preferred kinase sequence using the KINATEST-ID substrate predictive pipeline. The identified substrate sequence was used to synthesize and validate pan-FLT3 artificial substrates to monitor in vitro kinase activity in the presence of clinically relevant FLT3 TKI.

2019-01-07 | PXD011478 | Pride

A network-based approach reveals a novel mechanism of resistance to TKI-therapy in AML

Project description:Internal tandem duplications (ITDs) in the FLT3 gene are frequently identified and confer a poor prognosis in patient affected by acute myeloid leukemia (AML). The insertion site of the ITDs in FLT3 significantly impacts the sensitivity to tyrosine kinase inhibitors (TKIs) therapy, affecting patient’s clinical outcome. To decipher the molecular mechanisms driving the different sensitivity to TKIs therapy of FLT3-ITD cells, we used high-sensitive mass spectrometry-based (phospho)proteomics and deep sequencing. Here, we developed a novel generally-applicable data analysis strategy, dubbed “Signaling Profiler”, that supports the integration of unbiased large-scale datasets with literature-derived signaling networks. The approach resulted in the generation of FLT3-ITDs specific predictive models and reveales a crucial and conserved role of the WEE1-CDK1 axis in TKIs resistance. Remarkably, pharmacological inhibition of the WEE1 kinase significantly synergizes and strengths the pro-apoptotic effect of TKIs therapy in cell lines and patient-derived primary blasts. In conclusion, this work proposes a new molecular mechanism of TKIs resistance in AML and suggests a combination therapy as option to improve therapeutic efficacy.

2023-03-10 | PXD033953 | Pride

Clinical and biological characterization of children with FLT3-ITD-mutated acute myeloid leukemia

Project description:We examined if the minimal residual disease (MRD) and the Allelic Ratio (AR) of FLT3 internal tandem duplication (ITD) mutated patients may be prognostic factors. We correlated these parameters both with event free survival (EFS), with incidence of relapse and with gene expression profile (GEP). GEP showed that patients with high-ITD-AR or persistent MRD had different expression profiles. Results indicated that the ITD-AR levels and the MRD after I induction course are associated with transcriptional oncogenic profiles, which highlight differences in epigenetic control that may explain the variability in outcome among FLT3-ITD patients

2016-07-12 | GSE74183 | GEO

Differential expression analysis of primary AML cells treated with AC220 vs DMSO in endothelial cell co-culture.

Project description:Although chemotherapy can successfully induce remission in FLT3/ITD positive acute myeloid leukemia (AML) patients, many, especially those with a high ratio of the FLT3/ITD versus wild type allele (FLT3-AR), exhibit a high relapse rate, requiring hematopoietic stem cell (HSC) transplantation to increase the chance of long-term remission. As the bone marrow tumor microenvironment (TME) has been implicated in drug resistance, we reasoned that AML-TME interactions might be critical for leukemic precursor survival and drug resistance, and that targeting AML-TME interactions might be crucial to improving survival in FLT3/ITD AML patients. In this study, we demonstrate that endothelial cells (ECs), a component of the TME, and the Notch pathway plays a critical role in the protection of FLT3/ITD positive progenitors against AC220 in AML patient samples with high FLT3-AR. We have previously shown that high FLT3-AR disease is distinguished by the presence of the mutation in the least mature CD34+CD33- precursors, where leukemic stem cells (LSCs) reside. Here, we demonstrate that inhibiting Notch signaling overcomes the TME-mediated drug resistance of the LSC-enriched CD34+CD33- precursors, raising the possibility that Notch may serve as a therapeutic target for eradicating LSCs that are thought to be responsible for relapse in this high-risk AML subset.

2019-10-03 | GSE138340 | GEO

FLT3 inhibition upregulates HDAC8 via FOXO to inactivate p53 and promote maintenance of FLT3-ITD+ acute myeloid leukemia

Project description:Internal tandem duplication (ITD) mutations within the FMS-like receptor tyrosine kinase-3 (FLT3) can be found in up to 25~30% of acute myeloid leukemia (AML) patients and confer a poor prognosis. Although FLT3 tyrosine kinase inhibitors (TKIs) have shown clinical responses, the overall outcome of FLT3-ITD+ AML patients remains poor, and most of them would relapse very shortly. TKIs can not eliminate primitive FLT3-ITD+ AML cells, which are potential sources of relapse. Therefore, elucidating the mechanisms underlying FLT3-ITD+ AML maintenance and drug resistance is essential to develop novel, effective treatment strategies. Here, we demonstrate that FLT3 inhibition induces histone deacetylase 8 (HDAC8) upregulation through FOXO1 and FOXO3-mediated transactivation in FLT3-ITD+ AML cells. Upregulated HDAC8 deacetylates and inactivates p53, leading to leukemia maintenance and drug resistance upon TKIs treatment. Genetic or pharmacological inhibition of HDAC8 re-activates p53, abrogates leukemia maintenance and significantly enhances TKI-mediated elimination of FLT3-ITD+ AML cells. Importantly, in FLT3-ITD+ AML patient-derived xenograft models, the combination of FLT3 TKI (AC220) with a HDAC8 inhibitor (22d) significantly inhibits leukemia progression and effectively reduces primitive FLT3-ITD+ AML cells. Moreover, we extend these findings to an AML subtype harboring another tyrosine kinase activating mutation. In conclusion, our study demonstrates that HDAC8 upregulation as an important mechanism to resist TKIs and promote leukemia maintenance, and suggests that combining HDAC8 inhibition with TKI treatment could be a promising strategy to treat FLT3-ITD+ AML and other tyrosine kinase mutation-harboring leukemias.

2020-02-13 | GSE138057 | GEO

de novo childhood AML patients and FLT3 mutations.

Project description:This data set was used to study FLT3 wild type and mutants in childhood AML samples from the Pediatric Oncology Group Study 9421. Abstract: Fms-like tyrosine kinase 3 (FLT3) mutations are associated with unfavorable outcomes in children with acute myeloid leukemia (AML). We used DNA microarrays to identify gene expression profiles related to FLT3 status and outcome in childhood AML. Among 81 diagnostic specimens, 36 had FLT3 mutations (FLT3-MUs), 24 with internal tandem duplications (ITDs) and 12 with activating loop mutations (ALMs). In addition, 8 of 19 specimens from patients with relapses had FLT3-MUs. Predictive analysis of microarrays (PAM) identified genes that differentiated FLT3-ITD from FLT3-ALM and FLT3 wild-type (FLT3-WT) cases. Among the 42 specimens with FLT3-MUs, PAM identified 128 genes that correlated with clinical outcome. Event-free survival (EFS) in FLT3-MU patients with a favorable signature was 45% versus 5% for those with an unfavorable signature (P = .018). Among FLT3-MU specimens, high expression of the RUNX3 gene and low expression of the ATRX gene were associated with inferior outcome. The ratio of RUNX3 to ATRX expression was used to classify FLT3-MU cases into 3 EFS groups: 70%, 37%, and 0% for low, intermediate, and high ratios, respectively (P < .0001). Thus, gene expression profiling identified AML patients with divergent prognoses within the FLT3-MU group, and the RUNX3 to ATRX expression ratio should be a useful prognostic indicator in these patients. A clinical history design type is where the organisms clinical history of diagnosis, treatments, e.g. vaccinations, surgery etc. Computed

2006-01-06 | E-GEOD-3986 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

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