Ontology highlight
ABSTRACT:
PROVIDER: PRJEB41369 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR4844292.fastq.gz | Fastqsanger.gz | |||
| ERR4844293.fastq.gz | Fastqsanger.gz | |||
| ERR4844294.fastq.gz | Fastqsanger.gz | |||
| ERR4844295.fastq.gz | Fastqsanger.gz |
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Project description:BACKGROUND: BCR-ABL1+ chronic myeloid leukemia (CML) is characterized by abnormal production of leukemic stem (LSC) and progenitor cells and their spread from the bone marrow into the blood resulting in extramedullary myeloproliferation. So far, little is known about specific markers and functions of LSC in CML. METHODS: We examined the phenotype and function of CD34+/CD38─/Lin─ CML LSC by a multi-parameter screen approach employing antibody-phenotyping, mRNA expression profiling, and functional studies, including LSC repopulation experiments in irradiated NOD-SCID-IL-2Rgamma-/- (NSG) mice, followed by marker-validation using diverse control-cohorts and follow-up samples of CML patients treated with imatinib. RESULTS: Of all LSC markers examined, dipeptidylpeptidase IV (DPPIV=CD26) was identified as specific and functionally relevant surface marker-enzyme on CD34+/CD38─ CML LSC. CD26 was not detected on normal CD34+/CD38─ stem cells or LSC in other hematopoietic malignancies. The percentage of CD26+ CML LSC decreased to undetectable levels during successful treatment with imatinib in all patients (p<0.001). Whereas the sorted CD26─ stem cells obtained from CML patients engrafted irradiated NSG mice with multilineage BCR-ABL1-negative hematopoiesis, CD26+ LSC engrafted NSG mice with BCR-ABL1+ cells. Functionally, CD26 was identified as target-enzyme disrupting the SDF-1alpha-CXCR4-axis by cleaving SDF-1alpha a chemotaxin for CXCR4+ stem cells. Whereas CD26 was found to inhibit SDF-1alpha-induced migration, CD26-targeting gliptins reverted this effect and blocked the mobilization of CML LSC in a stroma co-culture assay. CONCLUSIONS: CD26 is a robust biomarker of LSC and a useful tool for their quantification and isolation in patients with BCR/ABL1+ CML. Moreover, CD26 expression may explain the extramedullary spread of LSC in CML. To define specific mRNA expression patterns and to identify specific LSC markers in CML LSC, gene array analyses were performed. RNA was isolated from sorted CD34+/CD45+/CD38─ CML LSC, CD34+/CD45+/CD38+ CML progenitor cells, CML MNC, sorted CD34+/CD38─ cord blood (CB) SC, CB-derived CD34+/CD38+ progenitor cells, and CB MNC. Total RNA was extracted from sorted cells using RNeasy Micro-Kit (Qiagen) and used (100 ng total RNA) for Gene Chip analyses. Preparation of terminal-labeled cRNA, hybridization to genome-wide human PrimeView GeneChips (Affymetrix, Santa Clara, CA, USA) and scanning of arrays were carried out according to the manufacturer's protocols (https://www.affymetrix.com). Robust Multichip Average (RMA) signal extraction and normalization were performed according to http://www.bioconductor.org/ as described.18 Differences in mRNA expression levels (from multiple paired samples) were calculated as mRNA ratio of i) CML LSC versus CB SC, ii) CML LSC versus CD34+/CD38+ CML progenitors, and normal cord blood SC versus cord blood progenitors. To calculate differential gene expression between individual sample groups where appropriate, we performed a statistical comparison using the LIMMA package as described previously. Briefly, LIMMA estimates the fold change between predefined sample groups by fitting a linear model and using an empirical Bayes method to moderate the standard errors of the estimated log-fold changes for each probe set.
2014-04-17 | E-GEOD-40721 | biostudies-arrayexpress
Project description:BACKGROUND: BCR-ABL1+ chronic myeloid leukemia (CML) is characterized by abnormal production of leukemic stem (LSC) and progenitor cells and their spread from the bone marrow into the blood resulting in extramedullary myeloproliferation. So far, little is known about specific markers and functions of LSC in CML. METHODS: We examined the phenotype and function of CD34+/CD38─/Lin─ CML LSC by a multi-parameter screen approach employing antibody-phenotyping, mRNA expression profiling, and functional studies, including LSC repopulation experiments in irradiated NOD-SCID-IL-2Rgamma-/- (NSG) mice, followed by marker-validation using diverse control-cohorts and follow-up samples of CML patients treated with imatinib. RESULTS: Of all LSC markers examined, dipeptidylpeptidase IV (DPPIV=CD26) was identified as specific and functionally relevant surface marker-enzyme on CD34+/CD38─ CML LSC. CD26 was not detected on normal CD34+/CD38─ stem cells or LSC in other hematopoietic malignancies. The percentage of CD26+ CML LSC decreased to undetectable levels during successful treatment with imatinib in all patients (p<0.001). Whereas the sorted CD26─ stem cells obtained from CML patients engrafted irradiated NSG mice with multilineage BCR-ABL1-negative hematopoiesis, CD26+ LSC engrafted NSG mice with BCR-ABL1+ cells. Functionally, CD26 was identified as target-enzyme disrupting the SDF-1alpha-CXCR4-axis by cleaving SDF-1alpha a chemotaxin for CXCR4+ stem cells. Whereas CD26 was found to inhibit SDF-1alpha-induced migration, CD26-targeting gliptins reverted this effect and blocked the mobilization of CML LSC in a stroma co-culture assay. CONCLUSIONS: CD26 is a robust biomarker of LSC and a useful tool for their quantification and isolation in patients with BCR/ABL1+ CML. Moreover, CD26 expression may explain the extramedullary spread of LSC in CML.
2014-04-17 | GSE40721 | GEO
Project description:Understanding leukemia heterogeneity is critical for the development of curative treatments as the failure to eliminate therapy-persistent leukemic stem cells (LSCs) may result in disease relapse. Here we have combined high-throughput immunophenotypic screens with large-scale single-cell gene expression analysis to define the heterogeneity within the LSC-population in chronic phase (CP) chronic myeloid leukemia (CML) patients at diagnosis and following conventional tyrosine kinase inhibitor (TKI) treatment. Our results reveal substantial heterogeneity within the putative LSC population in CP-CML and demonstrate differences in response to subsequent TKI-treatment between distinct subpopulations. Importantly, LSC subpopulations with myeloid and proliferative molecular signatures are proportionally reduced at a higher extent in response to TKI-therapy compared to subfractions displaying primitive and quiescent signatures. Additionally, cell surface expression of the CP-CML stem cell markers CD25, CD26 and IL1RAP is high on all subpopulation at diagnosis, but downregulated and unevenly distributed across subpopulations in response to TKI-treatment. The most TKI-insensitive cells of the LSC-compartment can be captured within the CD45RA- fraction and further defined as positive for CD26 in combination with an aberrant lack of cKIT expression. Thus, our results reveal the heterogeneity of the CML stem cell population and propose a Lin-CD34+CD38-/lowCD45RA-cKIT-CD26+ population to be targeted for improved therapy response.
2017-01-27 | GSE84507 | GEO
Project description:In an attempt to identify novel markers and immunologic targets in leukemic stem cells (LSC) in acute myeloid leukemia (AML) and chronic myeloid leukemia (CML), we screened samples of patients with AML, CML, and controls for expression of cell surface antigens on CD34+/CD38− and CD34+/CD38+ cells by multi-color flow cytometry. In addition, we examined mRNA expression profiles in highly purified CD34+/CD38− and CD34+/CD38+ cells by gene array- and qPCR analyses. Aberrantly expressed markers were identified in all patient cohorts examined.
2020-09-21 | GSE138883 | GEO
Project description:Leukemic stem cells (LSC) might be the source for leukemic disease self-renewal and account for disease relapse after treatment, which makes them a critical target for further therapeutic options. Leukemia associated antigens (LAA) might be suitable structures to be attacked by immunotherapeutic agents. We performed primary AML sample enrichment and microarray studies to define LAA expression levels in AML. We compared the LAA expression in the enriched CD34+CD38- AML fraction to that of enriched HSC of healthy donors and AML bulk cells (CD34+CD38+, CD34-CD38+ and CD34-CD38). Furthermore, we investigated the expression patterns of co-stimulatory molecules in LSC, bulk AML cells and enriched HSC, Conclusion: We demonstrated the differential expression of several LAA in LSC, and their suitability as target structures. We enriched primary AML samples using CD34 and CD38 as markers to compare LAA expression levels of LSC, HSC and AML bulk.
2015-04-23 | GSE68172 | GEO
Project description:Leukemic stem cells (LSC) might be the source for leukemic disease self-renewal and account for disease relapse after treatment, which makes them a critical target for further therapeutic options. Leukemia associated antigens (LAA) might be suitable structures to be attacked by immunotherapeutic agents. We performed primary AML sample enrichment and microarray studies to define LAA expression levels in AML. We compared the LAA expression in the enriched CD34+CD38- AML fraction to that of enriched HSC of healthy donors and AML bulk cells (CD34+CD38+, CD34-CD38+ and CD34-CD38). Furthermore, we investigated the expression patterns of co-stimulatory molecules in LSC, bulk AML cells and enriched HSC, Conclusion: We demonstrated the differential expression of several LAA in LSC, and their suitability as target structures. We enriched primary AML samples using CD34 and CD38 as markers to compare LAA expression levels of LSC, HSC and AML bulk. LAA expression profiles comparing LSC, HSC and leukemic bulk AML citation: Leukemic progenitor cells are susceptible to targeting by stimulated cytotoxic T cells against immunogenic leukemia-associated antigens Vanessa Schneider, Lu Zhang, Markus Rojewski, Natalie Fekete, Hubert Schrezenmeier, Alexander Erle, Lars Bullinger, Susanne Hofmann, Marlies Götz, Konstanze Döhner, Susann Ihme, Hartmut Döhner, Christian Buske, Michaela Feuring-Buske, Jochen Greiner
2015-04-23 | E-GEOD-68172 | biostudies-arrayexpress
Project description:MiR-142 is dynamically expressed and plays a regulatory role in hematopoiesis. Based on the simple observation that miR-142 levels are significantly lower in CD34+CD38- cells from blast crisis (BC) chronic myeloid leukemia (CML). CML patients compared with chronic phase (CP) CML patients (p=0.002), we hypothesized that miR-142 deficit plays a role in BC transformation. To test this hypothesis, we generated a miR-142 KO BCR-ABL (i.e., miR-142−/−BCR-ABL) mouse by crossing a miR-142−/− mouse with a miR-142+/+BCR-ABL mouse. While the miR-142+/+BCR-ABL mice developed and died of CP CML, the miR-142−/−BCR-ABL mice developed a BC-like phenotype in the absence of any other acquired gene mutations and died significantly sooner than miR-142+/+BCR-ABL CP controls (p=0.001). Leukemic stem cell (LSC)-enriched Lineage-Sca-1+c-Kit+ cells (LSKs) from diseased miR-142−/−BCR-ABL mice transplanted into congenic recipients, recapitulated the BC features thereby suggesting stable transformation of CP-LSCs into BC-LSCs in the miR-142 KO CML mouse. Single cell (sc) RNA-seq profiling showed that miR-142 deficit changed the cellular landscape of the miR-142−/−BCR-ABL LSKs compared with miR-142+/+BCR-ABL LSKs with expansion of myeloid-primed and loss of lymphoid-primed factions. Bulk RNA-seq analyses along with unbiased metabolomic profiling and functional metabolic assays demonstrated enhanced fatty acid β-oxidation (FAO) and oxidative phosphorylation (OxPhos) in miR-142−/−BCR-ABL LSKs vs miR-142+/+BCR-ABL LSKs. MiR-142 deficit enhanced FAO in miR-142−/−BCR-ABL LSKs by increasing the expression of CPT1A and CPT1B, that controls the cytosol-to-mitochondrial acyl-carnitine transport, a critical step in FAO. MiR-142 deficit also enhanced OxPhos in miR-142−/−BCR-ABL LSKs by increasing mitochondrial fusion and activity. As the homeostasis and activity of LSCs depend on higher levels of these oxidative metabolism processes, we then postulate that miR-142 deficit is a potentially druggable target for BC-LSCs. To this end, we developed a novel CpG-miR-142 mimic oligonucleotide (ODN; i.e., CpG-M-miR-142) that corrected the miR-142 deficit and alone or in combination with a tyrosine kinase inhibitor (TKI) significantly reduced LSC burden and prolonged survival of miR-142−/−BCR-ABL mice. The results from murine models were validated in BC CD34+CD38- primary blasts and patient-derived xenografts (PDXs). In conclusion, an acquired miR-142 deficit sufficed in transforming CP-LSCs into BC-LSCs, via enhancement of bioenergetic oxidative metabolism in absence of any additional gene mutations, and likely represent a novel therapeutic target in BC CML.
2023-01-13 | ST002446 | MetabolomicsWorkbench
Project description:Purpose: We previously demonstrated that immunophenotypically CD34-CD38- TKI resistant LSC/LIC population was clearly heterogeneous. The goal of this study is to explore more about the drug-resistant LSC/LICs Methods: CML patient cells were treated for 7 days with imatinib and live cells were subjected to scRNA-sequencing Results: scRNA-seq reveals heterogeneity in the therapy resistant cells. Distinct expression profiles, yet with an interrelated continuumsuggest the existence of a depply-quiescent persister population within resistant cells. Conclusions: In this study using single cell transcriptomics and single cell metabolomics analyses we identify and characterize a deeply-quiescent/persister CML LSC/LIC population subset of CML patient cells which is highly dependent on FAO for their metabolomic requierements
2023-06-16 | GSE206421 | GEO
Project description:Chronic myeloid leukemia is a disease originated at the level of hematopoietic stem cell, characterized by the abnormal overproduction and accumulation, both in blood and bone marrow, of myeloid cells. Treatment options include tyrosine kinase inhibitors that inhibit BCR-ABL activity, however some patients develop resistance to these drugs and has been asociated to the stem cells We have performed a comparative analysis of the global gene expression profiles between CML and normal HSCs. Our goal was to identify key genes and pathways –preferentially, or solely, expressed by LSCs- that could be used as markers for the identification and selection of LSC LSC(CD34+ CD38- lineage-negative cells), and as targets for inhibiting the growth of such cells. We have also analyzed the population of progenitor cells (CD34+ CD38+ Lin- cells) since it has been clearly shown that these cells play an important role in the pathophysiology of CML
2017-04-11 | GSE97562 | GEO
Project description:Tumors contain a fraction of cancer stem cells that maintain the propagation of the disease. The CD34CD38_ cells, isolated from acute myeloid leukemia (AML), were shown to be enriched leukemic stem cells (LSC). We isolated the CD34CD38_ cell fraction from AML and compared their gene expression profiles to the CD34CD38 cell fraction, using microarrays. We found 409 genes that were at least twofold over- or underexpressed between the two cell populations. These include underexpression of DNA repair, signal transduction and cell cycle genes, consistent with the relative quiescence of stem cells, and chromosomal aberrations and mutations of leukemic cells. Comparison of the LSC expression data to that of normal hematopoietic stem cells (HSC) revealed that 34% of the modulated genes are shared by both LSC and HSC, supporting the suggestion that the LSC originated within the HSC progenitors. We focused on the Notch pathway since Jagged-2, a Notch ligand was found to be overexpressed in the LSC samples. We show that DAPT, an inhibitor of gamma-secretase, a protease that is involved in Jagged and Notch signaling, inhibits LSC growth in colony formation assays. Identification of additional genes that regulate LSC self-renewal may provide new targets for therapy. Microarrays were used to compare the gene expression patterns between AML CD34+CD38- cells and AML CD34+CD38+
2011-12-01 | E-GEOD-34044 | biostudies-arrayexpress