Genome-wide comparison of gene expression level between leukemia stem cells in different tissues
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Haobin Ye
PROVIDER: E-GEOD-81842 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Similar Datasets
Project description:DNA Methyltransferase 3A (DNMT3A) is frequently mutated in various hematopoietic malignancies; however, the underlying oncogenic mechanisms remain elusive. Here, we report that DNMT3A mutational âhotspotâ at Arg882 (DNMT3A-R882H) cooperates with constitutively activated RAS in transforming murine hematopoietic stem/progenitor cells (HSPCs) ex vivo and inducing acute leukemias in vivo. DNMT3A-R882H potentiates aberrant transactivation of âstemnessâ gene expression programs, notably transcription factors Meis1, Hox-A, Mn1 and Mycn. Mechanistically, R882-mutated DNMT3A directly binds to cis-regulatory elements of these genes and induces focal CpG hypomethylation reminiscent of what was seen in human leukemias bearing DNMT3A R882 mutation. Furthermore, DNMT3A-R882H induced DNA hypomethylation facilitates gene enhancer/promoter activation and recruitment of Dot1l-associated transcription elongation machineries. Inactivation of Dot1l represses DNMT3AR882H-mediated stem cell gene dysregulation and acute leukemogenicity. In this dataset, we provided gene expression profiling data for (1) RH-RAS leukemia stem cells (RH-RAS LSCs), (2) LSCs transformed by MLL-AF9, (3) LSCs transformed by NUP98-JARID1A, and (4) Dot1l inhibitor-treated RH-RAS LSCs. Gene expression data were generated using Mouse Genome 430 2.0 Microarray (Affymetrix) for four independently derived RH-RAS LSC lines (termed as LSC RH-RAS #1, #2, #3 and #4), two RH-RAS LSC lines (LSC RH-RAS #1 and # 3) treated with 1 µM SGC0946 (a Dot1l-specific small-molecule inhibitor) for 4 days, one MLL-AF9-transformed progenitor line and three NUP98-JARID1A transformed progenitor lines.
2016-06-23 | E-GEOD-71439 | biostudies-arrayexpress
Project description:Beta-catenin signaling is required for establishment of leukemic stem cells (LSCs) in acute myeloid leukemia (AML), yet the upstream regulators that can augment this pathway are unknown. Through genome-wide gene expression analysis and functional studies, we identified an important role for GPR84 in MLL AML. Suppression of GPR84 significantly inhibited cell growth in pre-LSCs, reduced LSC frequency and impaired reconstitution of MLL AML. Furthermore, GPR84 conferred a growth advantage to Hoxa9/Meis1a transduced hematopoietic stem cells (HSCs). Our microarray analysis demonstrated that GPR84 overexpression significantly up-regulated a small set of MLL-fusion targets and beta-catenin co-effectors, and down-regulated a hematopoietic cell cycle inhibitor. These data thus reveal a previously unrecognized role of GPR84 in the maintenance of fully developed AML by sustaining aberrant beta-catenin signaling in LSCs. HSC-derived Hoxa9/Meis1a pre-LSCs were transduced with GPR84 cDNA or empty vector, and replated in methylcellulose supplemented with cytokines. Each group contains triplicate samples.
2014-10-15 | E-MTAB-1932 | biostudies-arrayexpress
Project description:Using a mouse model of chronic myelogenous leukemia (CML), here we report that HIF1M-NM-1 plays a crucial role in survival maintenance of leukemia stem cells (LSCs). Deletion of HIF1M-NM-1 impairs the propagation of CML through impairing cell cycle progression and inducing apoptosis of LSCs. Deletion of HIF1M-NM-1 results in elevated expression of p16Ink4a and p19Arf in LSCs, and knockdown of p16Ink4a and p19Arf rescues the defective colony-forming ability of HIF1M-NM-1-/- LSCs. To further identify the pathways in which Hif1a regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Hif1a-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+ cells, BCR-ABL-expressing wild type LSCs, and BCR-ABL-expressing Hif1a-/- LSCs. To identify genes that are regulated by BCR-ABL in LSCs and LSCs without the Hif1a gene, we compared the gene profile between wild type (WT) LSCs and Hif1a-/- LSCs.
2012-04-03 | E-GEOD-35111 | biostudies-arrayexpress
Project description:Using BCR-ABL-induced chronic myeloid leukemia (CML) as a disease model for leukemia stem cells (LSCs), we showed that BCR-ABL down-regulates the B lymphoid kinase (Blk) gene in leukemia stem cells in CML mice and that Blk functions as a tumor suppressor in LSCs and suppresses LSC function. Inhibition of this Blk pathway accelerates CML development, whereas increased activity of the Blk pathway delays CML development. To identify the pathways in which Blk regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL- and BCR-ABL-Blk expressing LSCs. This analysis revealed a large group of candidate genes that exhibited changes in the levels of transcription in the Blk expressing LSCs, and uncovered the molecular mechanisms by which Blk suppresses LSCs and CML development. Bone marrow cells were transduced with GFP, BCR-ABL-GFP or BCR-ABL-Blk-GFP, followed by transplantation into recipient mice. Fourteen days after transplantation, bone marrow cells were isolated and LSCs were sorted by FACS for isolation of total RNA for DNA microarray analysis.
2012-07-05 | E-GEOD-36096 | biostudies-arrayexpress
Project description:Little is known about the roles of Rictor/mTORC2 in the leukemogenesis of AML. Here, we demonstrated that Rictor is essential for the maintenance of MLL-driven leukemia by preventing LSCs from exhaustion. Rictor depletion led to a reactive activation of mTORC1 signaling by facilitating the assembly of mTORC1. Hyperactivated mTORC1 signaling in turn drove LSCs into cycling, compromised the quiescence of LSCs and eventually exhausted their capacity to generate leukemia. At the same time, loss of Rictor had led to a reactive activation of FoxO3a in leukemia cells, which acts as negative feedback to restrain greater over-reactivation of mTORC1 activity and paradoxically protects leukemia cells from exhaustion. Simultaneous depletion of Rictor and FoxO3a enabled rapid exhaustion of MLL LSCs and a quick eradication of MLL leukemia. As such, our present findings highlighted a pivotal regulatory axis of Rictor-FoxO3a in maintaining quiescence and the stemness of LSCs. To understand the critical molecular events caused by Rictor loss in MLL-AF9-driven leukemia,the K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MA9_R1,MA9_R2,MA9_R3) or control(MA9_C1,MA9_C2,MA9_C3), and subjected to microarray analysis on Affymetrix microarrays.Furthermore, the MLL-NRIP3-driven mice model was chosen for further examination.The K+Gâ mice BM cells were sorted from the 1st BMT of RictorÎ/Î(MN3_R1,MN3_R2,MN3_R3) or control(MN3_C1,MN3_C2,MN3_C3), and subjected to microarray analysis on Affymetrix microarrays.
2016-07-19 | E-GEOD-84505 | biostudies-arrayexpress
Project description:We previously demonstrated that Alox5 deficiency impairs the function of LSCs and prevents the initiation of BCR-ABL-induced CML. To identify the pathways in which Alox5 gene regulates function of LSCs, we performed a comparative DNA microarray analysis using total RNA isolated from non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. The result was validated by quantitative real-time PCR analysis of non-BCR-ABL-expressing Lin-Sca-1+c-Kit+, BCR-ABL-expressing wild type LSCs and BCR-ABL-expressing Alox5-/- LSCs. We have shown that Alox5 is a critical regulator of leukemia stem cells (LSCs) in a BCR-ABL-induced chronic myeloid leukemia (CML) mouse model, and we hypothesize that the Alox5 pathway represents a major molecular network that regulates LSC function. Therefore, we sought to further dissect this pathway by comparing the gene expression profiles of wild type and Alox5-/- LSCs derived from our mouse model for BCR-ABL-induced CML. DNA microarray analysis revealed a small group of candidate genes that exhibited changes in the levels of transcription in the absence of Alox5 expression. In particular, we noted that the expression of the Msr1 gene was up-regulated in Alox5-/- LSCs, suggesting that Msr1 might suppress the proliferation of LSCs. Using our CML mouse model, we show that Msr1 is down-regulated by BCR-ABL and this down-regulation is partially restored by Alox5 deletion, and that Msr1 deletion causes acceleration of CML development. Moreover, Msr1 deletion markedly increases LSC function through its effects on cell cycle progression and apoptosis. We also show that Msr1 affects CML development by regulating the PI3K-AKT pathway and ?-Catenin. Together, these results demonstrate that Msr1 suppresses LSCs and CML development. The enhancement of Msr1 function may be of significance in the development of novel therapeutic strategies targeting CML. To identify genes that are regulated by BCR-ABL in LSCs and LSCs without Alox5 gene, we compared the gene profile between wild type(WT) LSCs or Alox5-/- LSCs.
2011-05-17 | E-GEOD-29347 | biostudies-arrayexpress
Project description:ABL1 kinase inhibitors such as imatinib mesylate (IM) are effective in managing chronic myelogenous leukemia (CML) but incapable of eliminating leukemia stem cells (LSCs), suggesting that kinaseM-bM-^HM-^Rindependent pathways support LSC survival. Given that the bone marrow hypoxic microenvironment supports hematopoietic stem cells, we investigated if hypoxia similarly contributes to LSC persistence. Importantly, we found that while BCRM-bM-^HM-^RABL1 kinase remained effectively inhibited by IM under hypoxia, apoptosis became partially suppressed. Furthermore, hypoxia enhanced the clonogenicity of CML cells, as well as their efficiency in repopulating immunodeficient mice, both in the presence and absence of IM. HIF1M-bM-^HM-^RM-NM-1, which is the master regulator of the hypoxia transcriptional response is expressed in the bone marrow specimens of CML individuals. In vitro, HIF1M-bM-^HM-^RM-NM-1 is stabilized during hypoxia and its expression and transcriptional activity can be partially attenuated by concurrent IM treatment. Expression analysis demonstrates at the whole transcriptome level that hypoxia and IM regulate distinct subsets of genes. Functionally, knockdown of HIF1M-bM-^HM-^RM-NM-1 abolished the enhanced clonogenicity during hypoxia. Taken together, our results suggest that in the hypoxic microenvironment, HIF1M-bM-^HM-^RM-NM-1 signaling supports LSC persistence independently of BCRM-bM-^HM-^RABL1 kinase activity. Thus targeting HIF1M-bM-^HM-^RM-NM-1 and its pathway components may be therapeutically important for the complete eradication of LSCs. 24 samples consisting CD34+ bone marrow aspirates of 3 chronic phase patients that were subjected to 24h or 96h of DMSO/Normoxia (21% oxygen, 5% carbon dioxide) control, 2 M-BM-5M Imatinib, hypoxia (0.5% oxygen, 5% carbon dioxide) or combined Imatinib/hypoxia treatments in triplicate cultures.
2014-06-03 | E-GEOD-48294 | biostudies-arrayexpress
Project description:Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy driven largely by gene mutations and epigenetic modifications. The Nucleoporin 98kDa (NUP98) gene is a component of the nuclear pore complex that also plays a role as an intranuclear transcription scaffold. Fusion genes involving NUP98 have been recognized in a wide array of hematologic malignancy, most commonly AML4. Among over 30 partner genes known to be fused to NUP98 in human leukemia, NSD1 (for Nuclear receptor-binding SET Domain protein 1) (NSD1) is the most common. Patients with NUP98::NSD1 gene fusions have a poor prognosis, and the leukemic blasts frequently have an internal tandem duplication (ITD) of the FMS-related tyrosine kinase 3 gene (FLT3) gene accompanying the NUP98::NSD1 fusion. Previous reports have utilized BM transduction with retroviral vectors followed by transplantation into recipient mice to model AML driven by a NUP98::NSD1 fusion. Given that genetically engineered mice offer certain advantages over retroviral transduction models, such as consistent transgene expression and integration effects, lack of ionizing radiation, and transferability between investigators, we generated NUP98::Nsd1 transgenic mice.
2023-07-12 | GSE229501 | GEO
Project description:Analysis of gene expression of leukemia stem cells (LSCs) in different tissues. The hypothesis is that the distinct niche in different tissues affects the gene expression of LSCs.
2016-07-07 | GSE81842 | GEO
Project description:A leukemia cell fraction highly enriched for LSCs was generated in a mouse model of AML induced by co-expression of MLL target genes Hoxa9 and Meis1. Limit dilution transplantation analyses performed on various prospectively isolated leukemia cell subpopulations revealed that cells capable of transplanting AML to syngeneic recipient mice (the operational definition of LSCs) were highly enriched in the leukemia cell fraction displaying an immunophenotype (Lin- Sca1- c-kit+ CD16/32+ CD34+) comparable to normal GMPs, referred to as L-GMPs. For the purpose of identifying genes that are differentially expressed in LSCs, microarray expression profiling was performed on L-GMPs (from leukemic mice) and GMPs (from normal mouse BM) purified by flow cytometry.
2015-10-02 | GSE64773 | GEO