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Expression analysis of Kasumi-1 cells treated with or without FTY720

ABSTRACT: The clinical outcomes of M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) are poor. Here we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treatment of multiple sclerosis, showed great antitumorigenic activity against Kasumi-1 cell line, xenograft mouse model and leukemic blasts isolated from AML-M2 with t(8;21) patients. Primary investigation indicated that FTY720 caused cell apoptosis through caspase and protein phosphatase 2A (PP2A) activation. Transcriptomic profiling further revealed that FTY720 treatment could upregulate AML1 target genes and interfere with genes involved in ceramide synthesis. FTY720 treatment led to the elimination of AML1-ETO oncoprotein and caused cell cycle arrest. More importantly, FTY720 treatment resulted in rapid and significant increment of pro-apoptotic ceramide levels, determined by HPLC-ESI-MS/MS (high-performance liquid chromatography-electrospray ionization tandem mass spectrometry) based lipidomic approaches. Additionally, structural simulation model indicated that the directly binding of ceramide to inhibitor 2 of PP2A (I2PP2A) could reactivate PP2A and cause cell death. This study demonstrates, for the first time, that accumulation of ceramide plays a central role in FTY720 induced cell death of AML-M2 with t(8;21). Targeting sphingolipid metabolism by using FTY720 may provide novel insight into drug development for AML-M2 treatment. A six chip study using total RNA recovered from three separate cultures of DMSO-treated Kasumi-1 cells and three separate cultures of FTY720-treated Kasumi-1 cells.Each chip measures the expression level of genes from DMSO-/FTY720-treated Kasumi-1 cells.

ORGANISM(S): Homo sapiens

SUBMITTER: Junyan Lu

PROVIDER: E-GEOD-55772 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Expression analysis of Kasumi-1 cells treated with or without FTY720

Project description:The clinical outcomes of M2 subtype Acute Myeloid Leukemia (AML-M2) with t(8;21) are poor. Here we report that FTY720 (Fingolimod), a sphingosine analogue and an FDA approved drug for treatment of multiple sclerosis, showed great antitumorigenic activity against Kasumi-1 cell line, xenograft mouse model and leukemic blasts isolated from AML-M2 with t(8;21) patients. Primary investigation indicated that FTY720 caused cell apoptosis through caspase and protein phosphatase 2A (PP2A) activation. Transcriptomic profiling further revealed that FTY720 treatment could upregulate AML1 target genes and interfere with genes involved in ceramide synthesis. FTY720 treatment led to the elimination of AML1-ETO oncoprotein and caused cell cycle arrest. More importantly, FTY720 treatment resulted in rapid and significant increment of pro-apoptotic ceramide levels, determined by HPLC-ESI-MS/MS (high-performance liquid chromatography-electrospray ionization tandem mass spectrometry) based lipidomic approaches. Additionally, structural simulation model indicated that the directly binding of ceramide to inhibitor 2 of PP2A (I2PP2A) could reactivate PP2A and cause cell death. This study demonstrates, for the first time, that accumulation of ceramide plays a central role in FTY720 induced cell death of AML-M2 with t(8;21). Targeting sphingolipid metabolism by using FTY720 may provide novel insight into drug development for AML-M2 treatment.

2014-04-30 | GSE55772 | GEO

Addiction of t(8;21) and inv(16) AML to native RUNX1 [ChIP-Seq data]

Project description:Cancer cells maintain a sensitive balance between growth-promoting oncogenes and apoptosis inhibitors. We show that WT RUNX1 is required for survival of t(8;21)-Kasumi-1 and inv(16)-ME-1 AML cell lines. The malignant AML phenotype is sustained by a delicate AML1-ETO/RUNX1 balance that involves competition for common DNA binding sites regulating a subset of AML1-ETO/RUNX1 targets. Genomewide sequencing data is included herein: Transcription factors RUNX1 c-terminus and n-terminus which is shared with AML1-ETO were profiled independently), AML1-ETO and AP4 were profiled using ChIP-Seq in Kasumi-1 cells, as well as control ChIP-Seq experiments of non immune serum. Two replicates were performed for each transcription factor profiling and control experiment.

2013-08-18 | E-GEOD-45738 | biostudies-arrayexpress

Addiction of t(8;21) and inv(16) AML to native RUNX1 [Gene Expression data]

Project description:Cancer cells maintain a sensitive balance between growth-promoting oncogenes and apoptosis inhibitors. We show that WT RUNX1 is required for survival of t(8;21)-Kasumi-1 and inv(16)-ME-1 AML cell lines. The malignant AML phenotype is sustained by a delicate AML1-ETO/RUNX1 balance that involves competition for common DNA binding sites regulating a subset of AML1-ETO/RUNX1 targets. Genome expression was profiled after performing knockdown of RUNX1 and AML1-ETO in Kasumi-1 cells using specific siRNA-oligo nucleotides, and analyzed using Affymetrix Gene 1.0 ST arrays.

2013-08-18 | E-GEOD-45743 | biostudies-arrayexpress

Genome-wide map of JMJD1C binding in Kasumi-1 cells [ChIP-seq]

Project description:The AML1-ETO fusion protein, a transcription factor generated by the t(8;21) translocation in acute myeloid leukaemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a co-activator for AML1-ETO and is required for its transcriptional program. JMJD1C is directly recruited by AML1-ETO to its target genes and regulates their expression by maintaining low H3K9me2 levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for AML1-ETOâs ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors. Examination of JMJD1C and LYL1 chromatin binding in Kasumi-1 cells, HL-60 cells, NB-4 cells and THP-1 cells, including ChIP-seqs of JMJD1C and LYL1, and input DNAs for Kasumi-1, HL-60, NB4.

2015-11-02 | E-GEOD-63484 | biostudies-arrayexpress

RNA expression analysis upon JMJD1C depletion

Project description:The AML1-ETO fusion protein, a transcription factor generated by the t(8;21) translocation in acute myeloid leukaemia (AML), dictates a leukemic program by increasing self-renewal and inhibiting differentiation. Here we demonstrate that the histone demethylase JMJD1C functions as a co-activator for AML1-ETO and is required for its transcriptional program. JMJD1C is directly recruited by AML1-ETO to its target genes and regulates their expression by maintaining low H3K9me2 levels. Analyses in JMJD1C knockout mice also establish a JMJD1C requirement for AML1-ETOâs ability to increase proliferation. We also show a critical role for JMJD1C in the survival of multiple human AML cell lines, suggesting that it is required for leukemic programs in different AML cell types through its association with key transcription factors. Examination of RNA expression when Kasumi-1 cells are treated with control shRNA or two different JMJD1C shRNAs; in duplicate. Please note that the 'shAML1_ETO_vs_shControl.all_gene_exp.tb.txtl' was generated comparing control and shRNA treated RNA abundance-using previously published data [GSE43834; GSM1071857 and GSM1071852].

2015-11-02 | E-GEOD-63485 | biostudies-arrayexpress

MEIS2 is a novel oncogenic partner in AML1-ETO positive AML [RNA-Seq human]

Project description:MEIS2 collaborates with AML1-ETO in inducing acute myeloid leukemia in a murine bone marrow transplantation model RNA-seq to evaluate consequence of MEIS2 Knock-down on the transcriptional profle of the t(8;21) positive Kasumi-1 cell line

2016-07-04 | E-GEOD-81328 | biostudies-arrayexpress

Paired ChIP-Seq studies of Kasumi-1 t(8;21) AML cells

Project description:Nearly 10-15% of all acute myeloid leukemia (AML) cases are caused by a recurring chromosomal translocation between 8 and 21, t(8;21). The t(8;21) translocation generates the AML1-ETO leukemia fusion protein. AML1-ETO promotes leukemogenesis by transcriptionally dysregulating important cell-fate genes. Here, to better understand how AML1-ETO deregulates transcription, we performed paired ChIP-Seq analyses of sequence-specific transcription factors, coactivators, corepressors, HDACs, RNA Pol II and acetyl-histone marks in both control and AML1-ETO-depleted Kasumi-1 t(8;21) AML cells.

2020-02-14 | GSE131939 | GEO

miRNA profiling of human acute myeloid leukaemia Kasumi-1 cell line CD34+38- compartment.

Project description:The t(8;21) Acute Myeloid Leukaemia (AML) Kasumi-1cell line with N822K KIT mutation, is a model system for leukemogenesis. As AML initiating cells reside in the CD34+CD38- fraction, we addressed the refined cytogenomic characterization and miRNA expression of Kasumi-1 cell line and its FACS-sorted subpopulations focussing on this compartment. By conventional cytogenetics, Spectral Karyotyping and array-CGH the cytogenomic profile of Kasumi-1 cells evidenced only subtle regions differentially represented in CD34+CD38- cells. Expression profiling by a miRNA platform showed a set of miRNA differentially expressed in paired subpopulations and the signature of miR-584 and miR-182 upregulation in the CD34+CD38- fraction.

2010-02-19 | E-TABM-909 | biostudies-arrayexpress

A Stable Transcription Factor Complex Nucleated by Dimeric AML1-ETO Controls Leukaemogenesis

Project description:AML1-ETO, a fusion protein generated by the t(8;21) translocation in acute myeloid leukemia, is a transcription factor implicated in both gene repression and activation. We now show that, in leukemic cells, AML1-ETO resides in and functions through a stable protein complex (AETFC) that contains several hematopoietic transcription factors and cofactors. In conjunction with biochemical and leukemia pathological studies, the ChIP-seq and RNA-seq analyses of the AETFC components in leukemic cells reveal that these components stabilize the complex through multivalent interactions, provide multiple DNA-binding domains for diverse target genes, colocalize genome-wide, cooperatively regulate gene expression, and contribute to leukemogenesis. RNA-seq analyses gene expression upon knockdown of each AETFC component, including AML1-ETO, HEB, E2A, LYL1, LDB1 and LMO2, and double-knockdown of HEB and E2A, in Kasumi-1 cells. ChIP-seq analyses of four AETFC components, namely AML1-ETO, HEB, E2A and LMO2, in Kasumi-1 cells.

2013-06-20 | E-GEOD-43834 | biostudies-arrayexpress

RNAi profiling of human Kasumi-1 AML1-ETO knockdown samples

Project description:Kasumi-1 AML cells that were transfected in triplicate with AML1-ETO or luciferase siRNA constructs by either Amaxa nucleofection or Biorad siLentFect and incubated for 96 hours. Microarrays used to discover an AML1-ETO signature for a GE-HTS screen to identify AML1-ETO modulators. Experiment Overall Design: Kasumi-1 AML cells incubated for 96 hours after they were transfected in triplicate with AML1-ETO or luciferase siRNA constructs by either Amaxa nucleofection or Biorad siLentFect along with three control samples not transfected with a construct.

2009-05-11 | E-GEOD-15646 | biostudies-arrayexpress

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