GSK-3 inhibitor treatment effect on MLL leukemia cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE19736 | GEO | 2010/05/01
SECONDARY ACCESSION(S): PRJNA122197
REPOSITORIES: GEO
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Project description:Human leukemia cell line RS4.11 was treated with GSK-3 inhibitor SB216763 for 20 hours. Gene expression profiling was performed to analyze genes affected by GSK-3 inhibition. Human leukemia cell line RS4.11 was grown in vitro and treated with 10 uM GSK-3 inhibitor SB216763 or solvent DMSO for 20 hours. Total RNA was extracted and microarray analysis was performed. Two controls and three inhibitor treatment samples were analyzed.
2010-05-27 | E-GEOD-19736 | biostudies-arrayexpress
Project description:Gene expression data from AML cell lines, MOLM-14, U937, THP-1 and HL-60, that were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), or two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetic-based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3A (GSK-3A) in AML by performing two independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3A induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3AM-bM-^@M-^Sspecific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3B has been well studied in cancer development, these studies support a role for GSK-3A in AML. The AML cell lines, MOLM-14, U937, THP-1 and HL-60, were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), and two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6).
2012-02-27 | E-GEOD-35200 | biostudies-arrayexpress
Project description:Gene expression data from AML cell lines, MOLM-14, U937, THP-1 and HL-60, that were infected with a scrambled control hairpin (shControl), two shRNAs directed against GSK-3B (shGSK3B_1 and shGSK3B_2), or two shRNAs directed against GSK-3A (shGSK3A_5 and shGSK3A_6). Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults. Long-term survival of patients with AML has changed little over the past decade, necessitating the identification and validation of new AML targets. Integration of genomic approaches with small-molecule and genetic-based high-throughput screening holds the promise of improved discovery of candidate targets for cancer therapy. Here, we identified a role for glycogen synthase kinase 3A (GSK-3A) in AML by performing two independent small-molecule library screens and an shRNA screen for perturbations that induced a differentiation expression signature in AML cells. GSK-3 is a serine-threonine kinase involved in diverse cellular processes including differentiation, signal transduction, cell cycle regulation, and proliferation. We demonstrated that specific loss of GSK-3A induced differentiation in AML by multiple measurements, including induction of gene expression signatures, morphological changes, and cell surface markers consistent with myeloid maturation. GSK-3A–specific suppression also led to impaired growth and proliferation in vitro, induction of apoptosis, loss of colony formation in methylcellulose, and anti-AML activity in vivo. Although the role of GSK-3B has been well studied in cancer development, these studies support a role for GSK-3A in AML.
2012-02-27 | GSE35200 | GEO
Project description:Analysis of Multiple Myeloma Cell lines JJN-3 and RPMI gene expression following treated with GSK-J4 or Bortezomib Total RNA extracted from cells after 6 or 24 hour treatment with either GSK-J4, GSK-J5, Bortezomib or vehicle
2016-08-21 | E-GEOD-60600 | biostudies-arrayexpress
Project description:GSK-inhibitor treatment in IMR32 neuroblastoma cell line
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Project description:MLL fusion proteins in leukemia induce aberrant transcriptional elongation and associated chromatin perturbations, however the upstream signaling pathways and activators that recruit or retain MLL oncoproteins at initiated promoters are unknown. Through functional and comparative genomic studies, we identified an essential role for NF-kB signaling in MLL leukemia. Suppression of NF-kB led to robust anti-leukemia effects that phenocopied loss of functional MLL oncoprotein or associated epigenetic cofactors. The NF-kB subunit RELA occupies promoter regions of crucial MLL target genes and sustains the MLL-dependent leukemia stem cell program. IKK/NF-kB signaling is required for wild-type MLL and fusion protein retention and maintenance of associated histone modifications providing a molecular rationale for enhanced efficacy in therapeutic targeting of this pathway in MLL leukemias. MLL-AF10 cells were treated with 0.5µM IKK inhibitor or vehicle. Each group contains triplicate samples.
2013-09-19 | E-GEOD-46250 | biostudies-arrayexpress
Project description:MLL fusion proteins in leukemia induce aberrant transcriptional elongation and associated chromatin perturbations, however the upstream signaling pathways and activators that recruit or retain MLL oncoproteins at initiated promoters are unknown. Through functional and comparative genomic studies, we identified an essential role for NF-kB signaling in MLL leukemia. Suppression of NF-kB led to robust anti-leukemia effects that phenocopied loss of functional MLL oncoprotein or associated epigenetic cofactors. The NF-kB subunit RELA occupies promoter regions of crucial MLL target genes and sustains the MLL-dependent leukemia stem cell program. IKK/NF-kB signaling is required for wild-type MLL and fusion protein retention and maintenance of associated histone modifications providing a molecular rationale for enhanced efficacy in therapeutic targeting of this pathway in MLL leukemias.
2013-09-19 | GSE46250 | GEO
Project description:Analysis of Multiple Myeloma Cell lines JJN-3 and RPMI gene expression following treated with GSK-J4 or Bortezomib
2016-08-21 | GSE60600 | GEO
Project description:Thioneins are cysteine-rich, evolutionary conserved apoproteins that regulate divalent metal homeostasis by virtue of their metal-chelation properties resulting in the ligand-bound metallothionein state. Previous studies have demonstrated a transient upregulation (102- 103-fold) of a cluster of metallothionein genes as part of a transcriptional response to a class of histone demethylase tool compounds targeting human Fe2+ dependent ketoglutarate oxygenases KDM6A (UTX) and KDM6B (JmjD3). Exposure of multiple myeloma cells to the prototypic bioactive KDM6 inhibitor GSK-J4 induces apoptotic cell death and transcriptomic profiles that are dominated by metal and metabolic stress response signatures. We here investigate the hypothesis that the metal-chelating property of GSK-J4 provides the means for transport and intracellular release of Zn2+ leading to a metallothionein transcriptomic response signature. Live cell imaging upon myeloma cell exposure to GSK-J4 shows a transient increase of intracellular free Zn2+ concentrations upon KDM6 inhibitor treatment consistent with a model of inhibitor mediated metal transport. Comparison of KDM6 inhibitor and ZnSO4 treatments in the presence or absence of metal chelators show that both treatment conditions induce different transcription factor repertoires with an overlapping MTF1 transcriptional regulation responsible for metallothionein and metal ion transport regulation.
2022-09-16 | GSE213291 | GEO
Project description:The defining characteristics of leukemia, such as lineage and genetics, are associated with a typical age of onset. Understanding mechanisms of leukemia age specificity could improve disease models to develop new therapies. We used heterochronic transplantation of murine leukemia driven by MLL-AF9 to investigate the relative contribution of the age of the cell-of-origin or the hematopoietic microenvironment to the lineage fate of leukemia initiating cells (LICs). We show that the neonatal hematopoietic niche supports the development of infant-like mixed lineage B-cell/myeloid leukemia, while a mature niche promotes adult-like pure acute myeloid leukemia (AML) from identical cells of origin. We attribute this to inhibition of B-lymphoid fate in multipotent progenitor-like LICs by Ccl5 from adult bone marrow (BM) stroma, and implicate glycogen synthase kinase-3 (GSK-3) signaling in the myeloid fate specification in mouse and human MLL-driven leukemia. These findings connect maturation and aging of the hematopoietic system to leukemia age specificity.
2019-01-29 | GSE105086 | GEO