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Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Transcriptome dynamics of HL-60, NB4, and K562 cells under the ATRA treatment

ABSTRACT: Combination of new therapeutics with trans-retinoic acid (ATRA) could improve efficiency of acute myeloid leukemia (AML) treatment. Modeling the process of ATRA-induced differentiation based on transcriptomic profile of leukemic cells allows us to identify key molecules that could be affected to enhance the therapeutic effect of ATRA. Moreover, transcriptome analysis reveals the earliest steps of molecular response to inducer treatment. Thus, the transcriptomic profile of leukemic cells under the ATRA treatment at the different time points is considered as input data for further upstream regulator search.

ORGANISM(S): Homo sapiens

SUBMITTER: Svetlana Novikova

PROVIDER: E-MTAB-13723 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Proteome dynamics of HL-60, NB4, and K562 cells under the ATRA treatment

Project description:Searching for new strategies of acute myeloid leukemia (AML) treatment is of particular interest. Cell lines, e. g. HL-60 and NB4, represent model systems to study molecular features of leukemic cells. The all-trans-retinoic acid (ATRA) has proven itself to be an effective treatment for one of AML subtypes, i.e., acute promyelocytic leukemia (APL). At the same time, ATRA causes granulocytic differentiation of non-APL leukemic cells in vitro. Combination of new therapeutics with ATRA could improve efficiency of treatment. Studying the proteome perturbation in leukemic cells under the ATRA treatment allows to determine potential regulatory molecules that could be affected pharmacologically. Thus, the TMT-based proteomic profiles of HL-60, NB4, and K562 cell lines under the ATRA treatment were obtained at 0, 3, 12, 24, and 72 h after the ATRA treatment.

2024-06-23 | PXD050317 | Pride

Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [Illumina HumanHT-12 gene expression array]

Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. Overall, 30 specimens derived from HL-60 or TEX cell line were treated with drugs and hybridized to Illumina HumanHT-12 gene expression arrays.

2012-03-14 | E-GEOD-34672 | biostudies-arrayexpress

Human HL-60 Cells: all-trans retinoic acid (ATRA) vs. ATRA plus arsenic trioxide (ATO)

Project description:Transcriptional profiling of human leukemia?HL-60 cells comparing ATRA treated HL-60 cells with ATRA plus ATO. Goal was to determine the effects of ATO on ATRA induced differentiation of HL-60 cells. Two-condition experiment, ATRA vs. ATRA plus ATO treated HL-60 cells.

2015-03-31 | E-GEOD-67420 | biostudies-arrayexpress

A novel miRNA fingerprint inversely associated with breast cancer progression in SKBR3 cells challenged with all-trans retinoic acid and lapatinib

Project description:In SKBR3 cells, simultaneous targeting of RARM-kM-1 with all-trans retinoic acid (ATRA) and HER2 with lapatinib results in synergistic anti-tumor responses. SKBR3 cells were treated with vehicle (DMSO), lapatinib (100 nM), ATRA (100 nM) or lapatinib+ATRA for 36 hours and miRNA expression profile was determined by one-color Agilent microarray experiments.

2015-04-30 | E-MTAB-3097 | biostudies-arrayexpress

Inhibition of the LSD1 (KDM1A) demethylase reactivates the all-trans-retinoic acid differentiation pathway in acute myeloid leukemia [ChIP-Seq]

Project description:All-trans-retinoic acid (ATRA) has been successfully used in therapy of acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML) but the response of non-APL AML cases to ATRA-based treatment has been poor. Here we show that, via epigenetic reprogramming, inhibitors of LSD1/KDM1 demethylase including tranylcypromine (TCP) unlocked the ATRA-driven therapeutic response in non-APL AML. LSD1 inhibition did not lead to an increase in genome-wide H3 lysine4 dimethylation (H3K4me2) but did increase H3K4me2 and expression of myeloid differentiation-associated genes. Importantly, treatment with ATRA plus TCP dramatically diminished engraftment of primary human AML cells in vivo in NOD.SCID mice, suggesting that ATRA in combination with TCP may target leukemia-initiating cells. Furthermore, initiation of ATRA plus TCP co-treatment 15 days post-engraftment of human AML cells in NOD.SCID gamma mice also revealed the ATRA plus TCP drug combination to have a potent anti-leukemic effect, which was superior to treatment with either drug alone. These data identify LSD1 as a therapeutic target and strongly suggest that it may contribute to AML pathogenesis by inhibiting the normal pro-differentiative function of ATRA, paving the way for novel combinatorial therapies of AML. ChIP-seq was used to study the effects of ATRA, TCP and ATRA/TCP treatment on H3K4 dimethylation. In addition to the three treatment samples, two reference samples were processed: (i) An untreated sample using the same anti-H3K4me2 antibody and an untreated sample using IgG. These five sequencing experiments were conducted using HL-60 cells and TEX cells, leading to 10 ChIP-seq samples in total.

2012-03-14 | E-GEOD-34725 | biostudies-arrayexpress

Nuclear proteomics of induced granulocytic differentiation

Project description:The nuclear proteome harbors a sheer number of regulatory proteins, including transcription factors (TFs). Profiling of nuclear proteome during all-trans-retinoid acid(ATRA)-induced differentiation of HL60 cells allows to unveil molecular mechanisms of granulocytic maturation. It is especially important to have an understanding of molecular perturbations at the early stages of the differentiation process. Applying proteomic profiling using isobaric labeling coupled with alkaline fractionation (TMT/2D) we identified 1860 nuclear proteins with high confidence (FDR<0.01, at least 2 unique peptides per protein). Among them 136, 226, 280, 312 and 241 proteins were found to be altered at 3, 6, 9, 12, and 72 h in HL60 cell nuclear fraction under ATRA treatment.

2023-03-11 | PXD035281 | Pride

Isocitrate dehydrogenase 1 mutations prime the all-trans-retinoic acid myeloid differentiation pathway in acute myeloid leukemia HL-60 cells

Project description:Human acute myeloid leukemia HL60 cells were transduced with IDH1-WT or IDH1-R132H, and corresponding sub-clones were generated by FACS. In a first series of experiments, cells expressing wt and mutant IDH1were treated with either 1ÂµM all-trans retinoic acid (ATRA) or with vehicle (DMSO) for 24 hrs, resulting in 4 groups of samples (WT-CTRL, WT-ATRA, Mutant-CTRL, Mutant-ATRA). In a second series of assays, WT-IDH1 cells were pre-treated for 2 days with either 100 ÂµM octyl ester of (R)-2-hydroxyglutarate ((R)-2-HG) or 1-octanol (octyl), and then treated with 1 ÂµM ATRA or vehicle for 24 hrs, again resulting in 4 groups of samples (Octyl-CTRL, Octyl-ATRA, 2HG-CTRL, 2HG-ATRA). All assays were performed in triplicate (4 replicates for Mutant-CTRL and Mutant-ATRA).

2017-03-01 | E-MTAB-4327 | biostudies-arrayexpress

MicroRNAs and mRNAs differentially expressed in 5 glioblastoma spheroid cultures upon ATRA treatment

Project description:Microarray-based gene expression analysis identified microRNAs and mRNAs differentially expressed in 5 glioblastoma spheroid cultures upon ATRA treatment. In this study, a set of 5 glioblastoma spheroid cultures was used to acquire microRNA expression profiles, leading to the identification of differentially expressed microRNAs between untreated and ATRA-treated cultures. In this study, a set of 5 glioblastoma spheroid cultures was used to acquire expression profiles of a total of 16,651 transcripts, leading to the identification of differentially expressed genes between untreated and ATRA-treated cultures by Significance Analysis of Microarray data.

2010-07-20 | E-GEOD-17227 | biostudies-arrayexpress

Time-coursed transcriptomics of ATRA-induced granulocytic differentiation

Project description:Transcriptional profiling of HL-60 cells at 0, 3, 24, and 96 h after ATRA treatment. The differentially expressed genes was meant to be the input data for bioinformatic upstream regulator search

2021-09-01 | E-MTAB-10606 | biostudies-arrayexpress

Arsenic targets Pin1 and cooperates with retinoic acid to inhibit cancer-driving pathways and tumor-initiating cells

Project description:Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination safely cures fatal acute promyelocytic leukemia, but the mechanisms underlying their action and synergy remain elusive. ATRA inhibits APL, breast and liver cancers by targeting isomerase Pin1, a master regulator of oncogenic signaling. Here we show that ATO targets Pin1 and cooperates with ATRA to exert potent anticancer activity. ATO inhibits and degrades Pin1, and suppresses its oncogenic function by noncovalent binding to Pin1’s active site. ATRA increases cellular ATO uptake through upregulating aquaporin-9. ATO and ATRA, at clinically safe doses, cooperatively ablate Pin1 to block numerous cancer-driving pathways and inhibit the growth of triple-negative breast cancer cells and tumor-initiating cells in cell and animal models including patient-derived orthotopic xenografts, similar to Pin1 CRISPR knockout, which is substantiated by comprehensive protein and microRNA analyses. Thus, synergistic Pin1 inhibition by ATO and ATRA offers an attractive approach to combating breast and other cancers.

2018-10-16 | PXD010224 | Pride

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