Antitumor effect of FOXO1 inhibitor AS1842856 on B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE86067 | GEO | 2017/08/01
SECONDARY ACCESSION(S): PRJNA340164
REPOSITORIES: GEO
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Project description:We found that FOXO1 knock-down inhibits cell cycle progression and induces apoptosis in BCP-ALL cell lines RS4;11 and 018Z.
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Project description:Overwhelming evidence indicates that long non-coding RNAs have essential roles in tumorigenesis. Nevertheless, their expression and role in pediatric B-cell precursor acute lymphoblastic leukemia has not been extensively explored. Here, we conducted a comprehensive analysis of the long non-coding RNA transcriptome in ETV6/RUNX1 positive BCP-ALL, one of the most frequent subtypes of pediatric leukemia. An ETV6/RUNX1 expression signature was established, consisting of 596 lncRNAs (434 up and 162 down) using expression analysis of a series of primary patient samples. Subsequently, RNA sequencing from BCP-ALL cell lines and shRNA-mediated silencing of ETV6/RUNX1, illustrated that lnc-NKX2-3-1, lnc-TIMM21-5, lnc-ASTN1-1 and lnc-RTN4R-1 are bona fide ETV6/RUNX1 targets and could serve as novel biomarkers of this prevalent subtype of human leukemia.
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Project description:Hyperplasia (i.e., increased adipogenesis) contributes to excess adiposity, the hallmark of obesity that can trigger metabolic complications. As FoxO1 has been implicated in adipogenic regulation, we investigated the kinetics of FoxO1 activation during adipocyte differentiation, and tested the effects of FoxO1 antagonist (AS1842856) on adipogenesis. We found for the first time that the kinetics of FoxO1 activation follows a series of sigmoid curves, and reveals the phases relevant to clonal expansion, cell cycle arrest, and the regulation of PPARγ, adiponectin, and mitochondrial proteins (complexes I and III). In addition, multiple activation-inactivation transitions exist in the stage of terminal differentiation. Importantly, persistent inhibition of FoxO1 with AS1842856 almost completely suppressed adipocyte differentiation, while selective inhibition in specific stages had differential effects on adipogenesis. Our data present a new view of FoxO1 in adipogenic regulation, and suggest AS1842856 can be an anti-obesity agent that warrants further investigation.
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Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is caused by abnormal expansion of immature B cells. Genetic alterations can be identified in most of the BCP-ALL cases, however, some specific lesions including rearrangements of the mixed lineage leukemia (MLL) gene encoding lysine methyltransferase 2A (KMT2A) are associated with particularly poor prognosis. This MLL-rearranged subtype of leukemia poorly responds to conventional treatment and frequently undergoes a lymphoid-to-myeloid lineage switch in response to CD19-directed immunotherapy with consequent loss of B cell-specific targets for immunotherapy. Therefore, there is an urgent need to identify new targets for treatment of relapsed/refractory MLLr-BCP-ALL. Attractive targets may be found in a cell surfaceome, as membrane proteins are often expressed abnormally on cancer cells and are more accessible for therapeutics. Membrane proteins also play key roles in mediating external signaling and interactions with the microenvironment, thus being essential for cancer cell survival. RNA-based data may not always correlate with plasma membrane protein levels. Therefore, we performed the analysis of the BCP-ALL cell surfaceome by biotin labeling of plasma membrane proteins followed by tandem mass spectrometry (LC-MS/MS). This method requires high cell input and therefore was previously applied mainly to cell lines. However, the cell lines often do not fully represent primary samples due to genetic modifications and culture conditions. We have optimized the protocol of plasma membrane protein isolation and LC-MS/MS identification of patient-derived xenografts (PDXs) BCP-ALL cells. We confirmed the LC-MS/MS results by flow cytometry. Additionally, we compared the surfaceomes of PDXs BCP-ALL cells with BCP-ALL cell lines. We profiled six BCP-ALL PDXs and one cell line SEM, all with MLL translocations. In BCP-ALL PDXs we identified 1409 membrane-associated proteins, 945 of which were present in at least 3 samples. Tissue specificity analysis demonstrated that 93 of these proteins are specific for lymphoid cells, including already reported promising immunotherapeutic targets CD19, CD22, CD38, CD70, CD72, CD79A, and CD79B. The expression of selected proteins was confirmed by flow cytometry and compared to the expression on B-ALL cell lines with MLL translocation. Moreover, we identified an additional subset of proteins with potential therapeutic significance, including CD48, IL7R, ITGB7, LAIR1, LILRB1. Importantly, we observed profound differences between surfaceomes of BCP-ALL cell lines and PDX cells.
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Project description:B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is a heterogeneous disease that can be subdivided according to primary recurrent genetic abnormalities that are strongly associated with characteristic biological and clinical features. The detection of these abnormalities can facilitate diagnosis, risk stratification, and targeted therapy. We identified an unexpectedly high incidence of fusion genes involving ZNF384 genes, including TCF3-ZNF384, EP300-ZNF384, and CREBBP-ZNF384, in BCP-ALL of our cohort. We therefore used microarrays to evaluate the gene-expression characteristics of BCP-ALL harboring ZNF384-related fusion genes and compared with those of BCP-ALL with other types of conventional genetic abnormality.
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Project description:Activation of the transcription factor FOXO1 contributes to multiple pathological processes. The FOXO1 inhibitor AS1842856 demonstrated strong therapeutic effects in pre-clinical models of common diseases like diabetes and anthracyclines-induced heart failure. We have previously identified FOXO1 as a B-ALL dependency and demonstrated in in vivo B-ALL models that AS1842856 increased the survival and decreased B-ALL tumor load in all critical organ compartments, but most efficiently in the CNS. Here, we interrogated the underlying molecular mechanisms by comparison of the transcriptomic effects of AS1842856 and Foxo1-KO in a B-ALL mouse model. Despite the significant similarity in sets of regulated genes, we identified GSK3B inhibition as a signature enriched only in AS1842856-treated cells. Using an in vitro kinase assay, we identified AS1842856 as a direct GSK3B inhibitor that ultimately stabilizes CTNNB1. CTNNB1-KO partially protected B-ALL cell lines from the cytotoxic effect of AS1842856. At the same time, using a chemical protein degradation model, we found that FOXO1 indeed contributes to the cytotoxic effect of AS1842856. We conclude that AS1842856 targets two known B-ALL vulnerabilities: GSK3B and FOXO1. The unique mode of action, low toxicity, and ability to penetrate the blood-brain barrier warrant further investigation of the therapeutic potential of AS1842856 in B-ALL.
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Project description:In addition to genetic alterations, epigenetic abnormalities have been shown to underlie the pathogenesis of acute lymphoblastic leukemia (ALL)-the most common pediatric cancer. The purpose of this study was to characterize the whole genome DNA methylation profile in children with precursor B-cell ALL (BCP ALL) and to compare this profile with methylation observed in normal bone marrow samples. Additional efforts were made to correlate the observed methylation patterns with selected clinical features. We assessed DNA methylation from bone marrow samples obtained from 38 children with BCP ALL at the time of diagnosis along with 4 samples of normal bone marrow cells as controls using Infinium MethylationEPIC BeadChip Array. Patients were diagnosed and stratified into prognosis groups according to the BFM ALL IC 2009 protocol. The analysis of differentially methylated sites across the genome as well as promoter methylation profiles allowed clear separation of the leukemic and control samples into two clusters. 86.6% of the promoter-associated differentially methylated sites were hypermethylated in BCP ALL. Seven sites were found to correlate with the BFM ALL IC 2009 high risk group. Amongst these, one was located within the gene body of the MBP gene and another was within the promoter region- PSMF1 gene. Differentially methylated sites that were significantly related with subsets of patients with ETV6-RUNX1 fusion and hyperdiploidy. The analyzed translocations and change of genes' sequence context does not affect methylation and methylation seems not to be a mechanism for the regulation of expression of the resulting fusion genes.
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Project description:Basal-like breast cancer (BBC) is a poor prognosis cancer that lacks effective targeted therapy. Recently our group and others found that forkhead box transcription factor FOXO1 promotes stem gene expression in BBC and GBM cell lines. Given the critical role of cancer stem cells in promoting cancer progression, we examined the impact of FOXO1 inhibition with AS1842856 on BBC cells. We treated BT549 cells with 200nM AS1842856 for 48 hours and found that FOXO1 inhibition induced a set of WNT Pathway genes.
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