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Association of prognosis of acute myeloid leukemia patients with leukemia stem cell gene signature based on nucleostemin promoter activity

ABSTRACT: Acute myeloid leukemia (AML) is a heterogeneous neoplastic disorder, in which only a subset of cells have function as leukemia-initiating cells (LICs). In this study, we prospectively evaluated leukemia-initiating capacity of fractionated subpopulations of AML cells depending on expression of a nucleolar GTP binding protein, Nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model using a transgenic mouse, in which green florescence protein (GFP) is expressed under the control of particular region of NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukemia colonies in vitro, and exhibited high leukemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukemia-initiating capacity, i.e., leukemia stem cell gene signature. Furthermore, we found that the leukemia stem cell gene signature stratified human AML patients into two distinct clusters, reflecting prognosis. These data demonstrate that the mouse leukemia stem cell gene signature is significantly associated with malignant properties of human AML patients. Further analyses of gene regulation related with leukemia stem cells would provide novel insights for the progress in diagnostic and therapeutic approach of AML patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE58032 | GEO | 2014/07/30

SECONDARY ACCESSION(S): PRJNA248748

REPOSITORIES: GEO

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Association of prognosis of acute myeloid leukemia patients with leukemia stem cell gene signature based on nucleostemin promoter activity

Project description:Acute myeloid leukemia (AML) is a heterogeneous neoplastic disorder, in which only a subset of cells have function as leukemia-initiating cells (LICs). In this study, we prospectively evaluated leukemia-initiating capacity of fractionated subpopulations of AML cells depending on expression of a nucleolar GTP binding protein, Nucleostemin (NS). To monitor NS expression in living AML cells, we generated a mouse AML model using a transgenic mouse, in which green florescence protein (GFP) is expressed under the control of particular region of NS promoter (NS-GFP). In AML cells, NS-GFP levels were correlated with endogenous NS mRNA. AML cells with the highest expression of NS-GFP were very immature blast-like cells, efficiently formed leukemia colonies in vitro, and exhibited high leukemia-initiating capacity in vivo. Gene expression profiling analysis revealed that cell cycle regulators and nucleotide metabolism-related genes were highly enriched in a gene set associated with leukemia-initiating capacity, i.e., leukemia stem cell gene signature. Furthermore, we found that the leukemia stem cell gene signature stratified human AML patients into two distinct clusters, reflecting prognosis. These data demonstrate that the mouse leukemia stem cell gene signature is significantly associated with malignant properties of human AML patients. Further analyses of gene regulation related with leukemia stem cells would provide novel insights for the progress in diagnostic and therapeutic approach of AML patients. A mouse acute myeloid leukemia model was generated by introduction of HoxA9/Meis1 to bone marrow cells from a transgenic mouse, in which green florescence protein (GFP) is expressed under the control of particular region of NS promoter (NS-GFP).The leukemia cells were fractionated into 4 subpopulations based on NS-GFP level and c-Kit expression, (a) c-Kit-NS-GFPlow, (b) c-Kit-NS-GFPmiddle, (c) c-Kit+NS-GFPmiddle and (d) c-Kit+NS-GFPhigh cells.

2014-07-30 | E-GEOD-58032 | biostudies-arrayexpress

Proteomics investigation of Nucleostemin role in Nucleo-phosmin mutated OCI-AML 3 cell line

Project description:Nucleostemin (NS; product of the GNL3 gene) is a nucleolar/nucleoplasm shuttling GTPase whose levels are high in stem cells while rapidly decreasing upon differentiation. NS levels are also high in several solid and hematological neoplasms, including acute myeloid leukemia (AML). While a role in telomere maintenance, response to stress stimuli and in favoring DNA repair has been proposed in solid cancers, little or no information is available as to the role of nucleostemin in AML. Here we investigate this issue with a proteomics approach. We use as a model system the OCI-AML 3 cell line harboring a heterozygous mutation at the NPM1 gene, which is the most frequent driver mutation in AML (approximately 30% of total AML cases). We show that NS is highly expressed in this cell line but, contrary to what previously shown in other cancers, its presence is dispensable for cell growth and viability. However, proteomics analysis of OCI-AML 3 cell line before and after nu-cleostemin (NS) silencing showed several effects in different biological functions as highlighted by ingenuity pathway analysis (IPA). In particular, we report an effect in down-regulating DNA repair through homologous recombination and we confirmed higher DNA damage rate in OCI-AML 3 cells when NS is depleted, which considerably increases upon stress induced by the topoisomerase II inhibitor etoposide.

2022-08-11 | PXD034012 | Pride

Functional dissection of hematopoietic stem cell population by a stemness-monitoring system with NS-GFP transgene

Project description:Hematopoietic stem cells (HSCs) in a steady state are efficiently purified by the combination of several cell surface markers, however, such markers do not consistently reflect HSC activity. In this study, we successfully isolated functional HSCs by a unique stemness monitoring system using a transgenic mouse, in which green florescence protein (GFP) is driven by promoter/enhancer region of nucleostemin (NS) gene. We found that phenotypically defined long-term (LT)-HSC population exhibited the highest level of the NS-GFP intensity, whereas it was remarkably down-regulated during differentiation in vitro and in vivo. Importantly, among the LT-HSC population, the NS-GFPhigh cells significantly exhibited higher repopulating capacity than NS-GFPlow cells. Gene expression analysis revealed that 9 genes, including Vwf and Cdkn1c (p57), are highly expressed in NS-GFPhigh cells, which may represent signature of functional HSCs, i.e., stemness signature. When LT-HSCs suffered from remarkable stresses, such as transplantation or irradiation, NS-GFP intensity was downregulated, suggesting that NS-GFP accurately reflects HSC function. Finally, we found that functional HSCs were identified as NS-GFPhigh cells in CD34+ LSK cells, which has been recognized as progenitor cells without long-term reconstitution ability. Thus, high NS-GFP intensity represents stem cell characteristics in hematopoiesis and this system is useful for identification of uncharacterized HSCs.

2017-12-20 | GSE98500 | GEO

BCL6 mediates Chemoresistance in Acute Myeloid Leukemia

Project description:BCL6 is a transcription repressor that plays a crucial role in germinal center formation and lymphomagenesis. However, its role in myeloid malignancies remains unclear. Here, we explored the role of BCL6 in acute myeloid leukemia (AML). Heterogeneous levels of BCL6 were found across AML cell lines and primary AML samples. Cells with higher levels of BCL6 were indeed sensitive to treatment with BCL6 inhibitors. Gene expression profiling of AML cells treated with BCL6 inhibitor revealed a subset of target genes that are common with lymphoma cells. Ex vivo treatment of primary AML cells with BCL6 peptide inhibitor (BPI) induced apoptosis and decrease colony forming capacity which correlated with the levels of BCL6 expression . Importantly, inhibition of BCL6 in primary AML cells with either BPI or BCL6 siRNA resulted in significant reduction of leukemia initiating capacity using immunodeficient mice, suggesting ablation of leukemia stem cells (LSC). Such anti-LSC activity was also observed as downregulation of LSC gene signatures using gene expression analyses of cells treated with a BCL6 inhibitor. Importantly, treatment with cytarabine (AraC) induced BCL6 expression, and the levels of BCL6 induction were correlated with resistance to AraC. Treatment of AML primary derived xenografts (PDX) revealed that when AraC was combined with BCL6 inhibitor, inhibition of BCL6 significantly potentiated the efficacy of AraC and improved cytotoxic effects by interfering with the leukemia initiating capacity of AML cells. This suggests that pharmacological inhibition of BCL6 might provide a novel therapeutic strategy for ablation of LSCs and overcome chemoresistance in AML.

2020-08-01 | GSE133112 | GEO

miR-126 Governs Human Leukemia Stem Cell Quiescence and Therapeutic Resistance

Project description:In acute myeloid leukemia (AML), leukemia stem cells (LSC) play a central role in disease progression and recurrence due to their intrinsic capacity for self-renewal and chemotherapy resistance. Whereas epigenetic mechanisms balance normal blood stem cell self-renewal and fate decisions, mutation and dysregulation of epigenetic regulators are considered fundamental to leukemia initiation and progression. Alterations in miRNA function represent a non-canonical epigenetic mechanism influencing malignant hematopoiesis, however the function of miRNA in human LSC remains undetermined. Here we show that miRNA profiling of fractionated AML populations defines an LSC-specific signature that is highly prognostic for patient survival. Gain- and loss-of-function analyses demonstrated that miR-126 restrained cell cycle progression, prevented differentiation, and increased self-renewal of human LSC. By targeting the G0 to G1 gatekeeper CDK3, miR-126 preserved LSC quiescence and promoted chemotherapy resistance. Thus, in AML, miRNAs influence patient outcome through post-transcriptional regulation of stemness programs in LSC.

2016-03-31 | PXD001994 | Pride

AML1-ETO induced leukemia stem cell self-renewal depends on Plcg1

Project description:High-resolution proteomic analysis of acute myeloid leukemia (AML) stem cells identified phospholipase C- and Ca++-signaling pathways to be differentially regulated in AML1-ETO (AE) driven leukemia. Phospholipase C gamma 1 (Plcg1) could be identified as a direct target of the AE fusion. Genetic Plcg1 inactivation abrogated disease initiation by AE, reduced intracellular Ca++-release and inhibited AE-driven self-renewal programs. In AE-induced leukemia, Plcg1 deletion significantly reduced disease penetrance, number of leukemia stem cells and abrogated leukemia development in secondary recipient hosts. In human AE-positive leukemic cells inactivation of Plcg1 reduced colony formation and AML development in vivo. In contrast, Plcg1 was dispensable for maintenance of murine and human hematopoietic stem- and progenitor cells (HSPCs). Pharmacologic inhibition of Ca++-signaling downstream of Plcg1 resulted in impaired proliferation and self-renewal capacity in AE-driven AML. Thus, the Plcg1 pathway represents a novel specific vulnerability of AE-driven leukemia and poses an important new therapeutic target.

2022-01-12 | PXD011251 | Pride

Genome wide mapping of NR4A binding reveals cooperativity with ETS factors to promote epigenetic activation of distal enhancers in acute myeloid leukemia cells [array]

Project description:NR4As are critical tumor suppressors of acute myeloid leukemia (AML) whose expression is broadly silenced in leukemia initiating cell enriched populations from human patients relative to normal hematopoietic stem/progenitor cells. Rescued NR4A expression in human AML cells inhibits proliferation and reprograms AML gene signatures via transcriptional mechanisms that remain to be elucidated. By intersecting an acutely regulated, NR4A1 dependent transcriptional profile with genome wide NR4A binding distribution, we now identify an NR4A targetome of 685 genes that are directly regulated by NR4A1. We show that NR4As regulate gene transcription primarily through interaction with distal enhancers that are co-enriched for both NR4A1 and ETS transcription factor motifs. Using a subset of NR4A activated genes, we demonstrate that the ETS factors ERG and FLI-1 are required for activation of NR4A bound enhancers and NR4A target gene induction. NR4A1 dependent recruitment of ERG and FLI-1 promotes binding of p300 histone acetyl transferase to activate NR4A bound enhancers. These findings disclose novel epigenetic mechanisms by which NR4As and ETS factors cooperate to drive NR4A dependent gene transcription in human AML cells. Transcriptome analysis in triplicate 6hr after exogenous NR4A1 expression compared to GFP transfection control.

2016-03-22 | E-GEOD-79490 | biostudies-arrayexpress

Effect of genetic Zfx deletion on Myc induced gene expression in bone marrrow myeloid progenitors

Project description:Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) maintain the undifferentiated phenotype and proliferative capacity of their respective cells of origin, hematopoietic stem/progenitor cells and immature thymocytes. The mechanisms that maintain these progenitor-like characteristics are poorly understood. We report that the transcription factor Zfx is required for the development and propagation of experimental AML caused by MLL-AF9 fusion, and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx activated progenitor-associated gene expression programs and prevented differentiation. Key Zfx target genes included mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescued the propagation of Zfx-deficient AML. These studies identify a common mechanism that controls the cell-of-origin characteristics of acute leukemias derived from disparate lineages and transformation mechanisms. Bone marrow progenitors (c-Kit +) from Zfx wt/y CreER mice and Zfx fl/y CreER mice were harvested after tamoxifen administration to induce Cre. The Zfx wt and Zfx ko progenitors were infected with Myc expressing and control retrovirus with GFP selectable marker and cultured for 48 hours in cytokine supplemented media. The GFP + myeloid progenitors were sorted and cultured for another 4 days prior to RNA extraction.

2014-01-30 | E-GEOD-52416 | biostudies-arrayexpress

High ERG expression in human HSPCs promotes progenitor but not stem cell proliferation and molecular signatures that are enriched in high ERG leukemia.

Project description:ERG is an Ets-transcription factor required for normal blood stem cell development. High ERG expression in acute myeloid leukemia (AML) and acute T-cell lymphoblastic leukemia (T-ALL) is associated with a stem cell signature and poor prognosis. In murine over-expression models, human ERG is a potent oncogene that induces both T-ALL and AML. However the functional and molecular consequences of high ERG expression in normal hematopoietic stem/progenitors (HSPCs), and how this contributes to leukemia development, are unknown. Here we show that retroviral transduction of ERG into human CD34+ cells and maintenance of ERG at levels present in high ERG AML results in altered myeloid and T cell differentiation and an increase in the self-renewal capacity of transduced progenitors but not the more primitive stem cell compartment. Integrated analysis of genome-wide expression in high ERG CD34+ and ERG binding profiles in HSPCs revealed that these functional characteristics were accompanied by an expression signature that was enriched in normal HSCs, high ERG AMLs, early T-cell precursor (ETP)-ALLs and leukemic stem cell signatures associated with poor clinical outcome. The proliferative advantage of high ERG progenitors may provide a cellular context for the acquisition and propagation of mutations that contribute to the pathogenesis of leukaemia. RNA sequencing in ERG overexpressing human CD34+ cells

2014-10-31 | E-GEOD-53665 | biostudies-arrayexpress

FBXO9 in Murine Inversion 16 AML

Project description:The hematopoietic system is maintained throughout life by hematopoietic stem cells that are capable of differentiation to all hematopoietic lineages. An intimate balance between self-renewal, differentiation, and quiescence is required to maintain hematopoiesis. Disruption of this balance can result in hematopoietic malignancy, including acute myeloid leukemia (AML). FBXO9, from the F-box ubiquitin E3 ligases, is down-regulated in patients with AML compared to normal bone marrow. FBXO9 is a substrate recognition component of the Skp1-Cullin-F-box (SCF)-type E3 ligase complex. FBXO9 is highly expressed in hematopoietic stem and progenitor populations, which contain the tumor-initiating population in AML. In AML patients, decrease in FBXO9 expression is most pronounced in patients with the inversion of chromosome 16 (Inv(16)), a rearrangement that generates the transcription factor fusion gene, CBFB-MYH11. To study FBXO9 in malignant hematopoiesis, we generated a conditional knockout mouse model using a novel CRISPR/Cas9 strategy. Our data shows that deletion of Fbxo9 in mice expressing Cbfb-MYH11 leads to markedly accelerated and aggressive leukemia development. In addition, we find loss of FBXO9 leads to increased proteasome expression and tumors are more sensitive to bortezomib suggesting that FBXO9 expression may predict patient response to bortezomib treatment.

2019-11-27 | PXD014387 | Pride

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