Epigenetic profiles in normal haemopoietic and leukaemic cells.
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR746904.fastq.gz | Fastqsanger.gz | |||
| ERR746905.fastq.gz | Fastqsanger.gz | |||
| ERR746906.fastq.gz | Fastqsanger.gz | |||
| ERR746907.fastq.gz | Fastqsanger.gz | |||
| ERR746908.fastq.gz | Fastqsanger.gz |
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Project description:Lin-CD34+CD38+ and Lin-CD34-CD38- cells were isolated from 5 CML patients at diagnosis and 4 healthy donors.
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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.
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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.
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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
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Project description:Gene expression profiling of CD34/CD38 sorted CML cells
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Project description:CML stem cells (CMLSCs) and normal hematopoietic stem cells (HSCs) display the same set of surface markers (CD34+CD38-CD90+CD45RA-), making it infeasible to separate these two populations within the same sample. To overcome this challenge, and to minimize variations in gene expression due to individual variation, here we perform single-cell RNA-seq to compare expression profiles of CMLSCs and HSCs isolated from the same patient. We captured ~600 HSCs (CD34+CD38-CD90+CD45RA-) (~200 from each of three CML patient samples), separated them into CMLSCs (BCR-ABL+) or normal HSCs (BCR-ABL-) based on the presence of the BCR-ABL transcript, and performed paired-end deep sequencing. Typically, we obtained ~2.5 million mapped reads (>70% average mapping efficiency) and detected ~5,000 genes (transcript per million [TPM]>1) per cell. Despite the heterogeneity of the gene expression pattern, we were able to identify genes that were significantly more highly expressed in CMLSCs than in normal HSCs. Notably, among these genes are two cell surface markers, CD33 and CD47, that could potentially be used to distinguish CMLSCs from normal HSCs. We also found genes, such as PIM2, that could be targeted for CML therapy using available small molecule inhibitors.
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Project description:We here by prospectively characterizing BM stormal cells from healthy donors and patients with chornic myeloid leukemia (CML) have found that CXCL14 is dysregulated in CML patient bone marrow niche. Further, CXCL14 promotes TKI therapy response to CML LSCs in vitro and in vivo. To further determine the molecular mechanisms of CXCL14 action, we performed RNA sequencing of CML CD34+CD38- cells 6-24h post stimulation with conditioned media (CM) derived from either NIH3-CTRL or NIH3-CXCL14 cells.
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Project description:This study compares the epigenetic signatures of CD34+ cells from chronic phase chronic myeloid leukemia (CML) samples and blast phase CML samples v.s. normal CD34+ cells from cord blood and adult bone marrow samples. H3K27me3 genomic loci were detected by ChIP-seq.
2021-11-08 | GSE188241 | GEO
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.
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Project description:In chronic myeloid leukemia (CML) neoplastic stem cells (NCS) represent a critical target of therapy. However, little is known about markers and targets expressed in CML NSC. 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, followed by marker-validation using diverse control-cohorts and follow-up samples of CML patients treated with imatinib. We here show that in contrast to normal stem cells, CD34+/CD38− CML NSC express IL2RA (CD25), and that STAT5 induces expression of CD25 in Lin−/Sca-1+/Kit+ NSC (LSK) in C57/Bl6 mice. Correspondingly, expression of CD25 decreased in the human BCR/ABL1+ stem cell line KU812 upon shRNA-induced STAT5-depletion. The BCR/ABL1-inhibitors nilotinib and ponatinib were also found to decrease STAT5 activity and CD25-expression in KU812 cells and primary CML NSC. A CD25-targeting shRNA augmented the proliferation of KU812 cells in vitro and in vivo in NOD/SCID-IL2R-/- mice. In consecutive experiments the PI3K/mTOR-blocker BEZ235 was found to promote STAT5- and CD25 expression and to produce synergistic anti-neoplastic effects with nilotinib and ponatinib in CML cells. Together, CD25 is a novel STAT5-dependent marker and target in CML NSC.
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