Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Posttranslational splicing modifications as a key mechanism in cytarabine resistance in AML

ABSTRACT: Despite the approval of several drugs for AML, cytarabine is still widely used as a therapeutic approach. However, most patients show resistance and only 10% of them overcome the disease. Using high-throughput screening analysis, we show that phosphorylation levels of SR proteins were elevated during cytarabine resistance. Moreover, phosphorylation of SR proteins at diagnosis was different between responder and non-responder patients, pointing to their utility to predict response. These changes correlated with altered transcriptomic profiles of SR protein target genes.

INSTRUMENT(S): impact

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Eduardo Zarzuela

LAB HEAD: Javier Muñoz Peralta

PROVIDER: PXD034010 | Pride | 2023-07-04

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
	20170712_EZ_MLin_Phos_1_2-A_1_01_10763.d.zip	Other
	20170712_EZ_MLin_Phos_1_2-A_1_01_10771.d.zip	Other
	20170712_EZ_MLin_Phos_2_2-A_2_01_10764.d.zip	Other
	20170712_EZ_MLin_Phos_2_2-A_2_01_10772.d.zip	Other
	20170712_EZ_MLin_Phos_3_2-A_3_01_10765.d.zip	Other

Items per page:

1 - 5 of 39

Similar Datasets

AML patients for in vivo study of venetoclax plus AraC treatment

Project description:Therapy resistance represents a major clinical challenge in acute myeloid leukemia (AML). Here we define a “MitoScore” signature that identifies high mitochondrial oxidative phosphorylation (OxPHOS) in vivo and in AML patients. Primary AML cells with cytarabine (AraC) resistance and high MitoScore relied on mitochondrial Bcl2 and were highly sensitive to venetoclax (VEN) plus AraC (but not to VEN plus azacytidine, AZA). Single-cell transcriptomics of VEN+AraC-residual cell populations revealed adaptive resistance associated with changes in OxPHOS, electron transport chain complex (ETC) and the TP53 pathway.

2021-11-12 | GSE183329 | GEO

Role of intratumoral CD11b+ cells in immune checkpoint resistance in GBM

Project description:Glioblastomas show low response rates to immune checkpoint blockade with few hypermutated glioblastomas showing responses. Moreover, a growing body of evidence suggests that macrophages in the glioblastoma microenvironment impair anti-tumor immunity and immunotherapy approaches. Here, we investigate macrophage-mediated mechanisms of response and resistance to combinatory immune checkpoint blockade targeting PD-1 and CTLA-4 in the murine syngeneic Gl261 glioblastoma model. Nanostring analysis from CD45highCD11b+ cells isolated from ICB responder and non-responder Gl261 tumors was performed. Here, we provide evidence for a differential expression of pro- and anti-inflammatory genes in CD45highCD11b+ cells from ICB responder and non-responder tumors pointing towards a suppressive phenotype of ICB non-responder CD45highCD11b+ cells. Targeting these suppressive CD45highCD11b+ cells in the glioblastoma microvenvironment might thus potentiate ICB efficacy.

2020-02-03 | GSE129877 | GEO

Adverse stem cell features in a single AML sample predict clinical outcome in AML patient cohorts

Project description:Patients with acute myeloid leukemia (AML) suffer dismal prognosis and the most adverse subpopulation within each tumor determines patient’s prognosis. To better understand challenging features in AML, we studied individual stem cells from a single AML sample, complementing genomic with in vivo functional studies. Primary tumor cells from an AML patient’s first and second relapse were transplanted into NSG mice to establish serially transplantable patient derived xenografts (PDX). In an innovative approach, twelve derivative PDX clones were generated thereof, each derived from a single AML stem cell as proven by molecular barcoding, and were color-marked to facilitate multiplex competitive in vivo assays. PDX clones consisted of four different genomic clusters; one cluster displayed resistance against Cytarabine treatment, while two other clusters harbored increased stem cell potential, indicating that stemness and treatment resistance had evolved independently in the sample. In vivo functional data correlated closely with the phylogenetic tree calculated from exome data. The Cytarabine-resistant cluster was characterized by a distinct gene expression profile, and a score thereof predicted outcome in large clinical patient data cohorts. Taken together, we provide proof of concept that intra-sample heterogeneity mimics inter-sample heterogeneity in AML. Stem cell disparities within a single sample allow insights into adverse characteristics of general importance for AML.

2022-04-04 | PXD026296 | Pride

Targeting cell cycle and apoptosis to overcome chemoresistance in AML

Project description:A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockout of cyclin dependent kinase inhibitor 2A (CDKN2A) as contributing to resistance. To investigate the therapeutic potential of upregulating CDKN2A expression using WM-1119 and further elucidate its mechanism of action, we performed RNA-seq on WM-1119- (or vehicle control) treated OCI-AML3 cells with or without CRISPR mediated genetic depletion of CDKN2A.

2022-11-22 | GSE205802 | GEO

FOXM1-AKT positive regulation loop provides venetoclax resistance in AML

Project description:FOXM1 and AKT are crucial pro-oncogenic regulators of cancer therapy resistance. Due to reciprocal regulatory links they establish a positive feedback autoregulation loop in AML cells. Disruption of this loop via inhibition of either FOXM1 or AKT results in similar gene expression changes, drastic upregulation of HOXA genes and sensitization of AML cells to cytarabine and venetoclax treatment.

2021-08-18 | GSE172189 | GEO

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones

Project description:Understanding the contribution of abnormal genetic and epigenetic programs to acute myeloid leukemia (AML) is necessary for the integrated design of targeted therapies. To investigate this, we determined the effect of epigenetic reprogramming on leukemic behavior by generating induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements. AML-derived iPSCs (AML-iPSCs) retained leukemic mutations, but reset leukemic DNA methylation/gene expression patterns and lacked leukemic potential. However, when differentiated into hematopoietic cells, AML-iPSCs reacquired the ability to give rise to leukemia in vivo and reestablished leukemic methylation/gene expression patterns, including an aberrant MLL signature, indicating that epigenetic reprogramming was insufficient to eliminate leukemic behavior. In one case, we identified distinct AML-iPSC KRAS mutant and wildtype subclones that demonstrated differential growth properties and therapeutic susceptibilities, predicting KRAS wildtype clonal relapse due to increased cytarabine resistance. Increased cytarabine resistance was further observed in a cohort of KRAS wildtype MLL-rearranged AML samples, demonstrating the utility of AML-iPSCs in predicting subclonal relapse and facilitating clonal targeting in AML. This SuperSeries is composed of the SubSeries listed below.

2016-11-14 | GSE89778 | GEO

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [methylation]

2016-11-14 | GSE89776 | GEO

Pluripotent Reprogramming of Human AML Resets Leukemic Behavior and Models Therapeutic Targeting of Subclones [RNA-seq]

2016-11-14 | GSE89777 | GEO

Targeting mitochondrial structure sensitizes AML to Venetoclax

Project description:The BCL-2 family plays important roles in acute myeloid leukemia (AML) and Venetoclax, a selective BCL-2 inhibitor, has received FDA approval for treatment of AML. However, drug resistance ensues after prolonged treatment, highlighting the need for a greater understanding of the underlying mechanisms. Using a genome-wide CRISPR/Cas9 screen in human AML, we identified genes whose inactivation sensitizes AML blasts to Venetoclax. Genes involved in mitochondrial organization and function were significantly depleted throughout our screen, including the mitochondrial chaperonin CLPB. We demonstrated that CLPB is upregulated in human AML, it is further induced upon acquisition of Venetoclax resistance and its ablation sensitizes AML cells to Venetoclax. Mechanistically, CLPB maintains the mitochondrial cristae structure via its interaction with the cristae-shaping protein OPA1, whereas its loss promotes apoptosis by inducing cristae remodeling and mitochondrial stress responses. Overall, our data suggest that targeting mitochondrial architecture may provide a promising approach to circumvent Venetoclax resistance.

2019-05-03 | GSE125403 | GEO

Gene expression signatures in ex vivo Cytarabine (Ara-C) and Daunorubicin (Dnr) sensitive AML samples

Project description:Wide inter-individual variation in terms of outcome and toxic side effects of treatment exist among patients with AML receiving chemotherapy with cytarabine (Ara-C) and daunorubicin (Dnr). Drug resistance and relapse are considered major causes of treatment failure. Gene expression profiling was undertaken to address possible mechanisms of Ara-C/Dnr resistance. Based on ex vivo Ara-C cytotoxicity at diagnosis, Ara-C sensitive (IC50 <3uM AraC) and Dnr sensitive samples (IC50 < 0.5 uM) (5 samples each) were included for microarray analysis. These were compared with the samples which were drug resistant ex vivo at diagnosis. Our microarray experiment resulted in indentifying differentially expressed genes under ex vivo Ara-C sensitive as well as Dnr sensitive samples compared to ex vivo Drug resistant samples. One-color experiment,Organism: Homo sapiens, Custom Human Whole Genome 8x60k Array designed by Genotypic Technology Private Limited (AMADID: 27114), Labeling kit: Agilent Quick-Amp labeling Kit (p/n5190-0442)

2016-07-04 | E-GEOD-52919 | biostudies-arrayexpress