Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Chronic myeloid leukaemia stem cells present an aberrant gene expression signature that is not affected by tyrosine kinase inhibitors

ABSTRACT: Tyrosine kinase inhibitors (TKI) revolutionised the treatment of CML at the beginning of the century. However, TKI do not eliminate the leukaemia stem cells, which can reinitiate the disease upon treatment withdrawal. Thus, finding new therapeutic targets in CML stem cells is key to find a curative treatment. Using microarray datasets, we defined a list of 227 genes which were differentially expressed in CML stem cells compared to healthy controls but were not affected by TKI. Two of them, CD33 and PPIF, are targeted by gemtuzumab-ozogamicin and cyclosporin A, respectively. We treated CML and control CD34+ cells with either drug with or without imatinib to investigate the therapeutic potential of the TKI independent gene expression signature. Cyclosporine A in combination with imatinib reduced the number of CML CFC compared with non-CML controls, but at concentrations not achievable in the clinical practice. Gemtuzumab-ozogamicin showed a EC50 of 146ng/mL, well below the plasma peak concentration of 630ng/mL observed in AML patients and below the EC50 of 3247ng/mL observed in non-CML cells. Interestingly, gemtuzumab-ozogamicin seems to promote cell cycle progression in CML CD34+ cells and we found it to activate the RUNX1 pathway in a RNAseq experiment. This suggests that targeting the tyrosine kinase inhibitor independent gene expression signature in CML stem cells could be exploited for the development of new therapies in CML.

ORGANISM(S): Homo sapiens

PROVIDER: GSE198576 | GEO | 2022/11/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Early and late TKI response of CML stem cells

Project description:Chronic myeloid leukaemia (CML) is a clonal haemopoietic stem cell (HSC) disorder associated with the BCR-ABL oncogene, which encodes a constitutively active tyrosine kinase. We have demonstrated the existence of CML HSC which are resistant to the tyrosine kinase inhibitors (TKI). We have hypothesised that CML stem cells are dependent on key survival pathways that are induced by TKI treatment. In order to elucidate these key survival pathways, we have investigated the transcriptional differences between CML stem/progenitor cells (CD34+38-) treated with TKIs (imatinib, dasatinib and nilotinib) at different time points (8 hours and 7 days, in the absence of growth factors) and by carrying out RNA profiling for the different populations. CD34+38- cells were isolated from chronic phase patient samples. >100ng of total RNA was amplified prior to analysis that was carried out with Affymetrix Human Gene 1.0 ST array.

2018-01-20 | E-MTAB-2594 | biostudies-arrayexpress

microRNA expression profiling of CML and normal quiescent cells.

Project description:Chronic myeloid leukaemia (CML) is a clonal haemopoietic stem cell (HSC) disorder associated with the BCR-ABL oncogene, which encodes a constitutively active tyrosine kinase. We have demonstrated the existence of CML HSC which are resistant to the tyrosine kinase inhibitors (TKI). We have hypothesised that CML stem cells are dependent on key survival pathways that are induced by TKI treatment. In order to elucidate these key survival pathways, we have investigated the transcriptional differences between normal and CML stem/progenitor cells (CD34+38-) and by carrying out RNA profiling for the different populations. CD34+38- cells were isolated from chronic phase patient samples. LCSciences human miRNA microarray chips were used (100% coverage of mature miRNAs listed in miRBase version 14).

2018-01-12 | E-MTAB-3220 | biostudies-arrayexpress

Pyruvate Anaplerosis is a Targetable Vulnerability in Persistent Leukaemic Stem Cells

Project description:Deregulated oxidative metabolism is a hallmark of leukaemia. While use of tyrosine kinase inhibitors (TKIs) such as imatinib has led to increased survival of chronic myeloid leukaemia (CML) patients, it fails to eradicate disease initiating leukemic stem cells (LSCs). Whether TKI-treated CML LSCs remain metabolically deregulated is unknown. Using clinically and physiologically relevant assays we generated multi-omics datasets that offer unprecedented insight into nutrient fate in patient derived CML LSCs. We demonstrate that LSCs have increased glucose anaplerosis when compared to normal hematopoietic stem cells. While imatinib treatment reverses BCR-ABL-mediated LSC metabolic reprogramming, stable isotope-assisted metabolomics revealed that deregulated glucose anaplerosis is unaffected by imatinib. Encouragingly, genetic ablation of glucose anaplerosis sensitises CML cells to imatinib. Finally, we demonstrate that the clinical oral-available inhibitor MSDC-0160 targets glucose anaplerosis in robust pre-clinical CML models. Collectively these results highlight glucose anaplerosis as a persistent and therapeutically targetable vulnerability in imatinib-treated CML patient samples.

2023-06-27 | GSE216837 | GEO

Whole transcriptome sequencing for wild type and IRAIN over-expression K562 cells

Project description:The development of tyrosine kinase inhibitors (TKIs) has revolutionarily increased the overall survival of patients with chronic myeloid leukemia (CML). However, drug resistance remains a major obstacle. Here, we demonstrated that a BCR-ABL1-independent long non-coding RNA, IRAIN, is constitutively expressed at low levels in CML, resulting in imatinib resistance. IRAIN knockdown decreased the sensitivity of CD34+ CML blasts and cell lines to imatinib, whereas IRAIN overexpression significantly increased sensitivity. Mechanistically, IRAIN downregulates CD44, a membrane receptor favorably affecting TKI resistance, by binding to the nuclear factor kappa B subunit p65 to reduce the expression of p65 and phosphorylated p65. Therefore, the demethylating drug decitabine, which upregulates IRAIN, combined with imatinib, formed a dual therapy strategy which can be applied to CML with resistance to TKIs.

2024-04-13 | GSE263645 | GEO

Transcriptome profiling of fenretinide-treated and untreated CD34+ cells from 4 CML patients

Project description:Imatinib, as the first-line agent of chronic myeloid leukemia (CML), is ineffective in eradicating CML stem/progenitor cells, thus unable to prevent late relapse. Here we present data indicating that fenretinide preferentially targets CD34+ CML cells and enhances the efficacy of imatinib in CML. As tested by colony forming cell assays, both number and size of total colonies derived from CD34+ CML cells were significantly reduced by fenretinide, and by combining fenretinide with imatinib. In particular, colonies derived from erythroid progenitors and those derived from more primitive pluripotent progenitor cells were highly sensitive to fenretinide/fenretinide plus immtinib. Further data showed that fenretinide was able to induce apoptosis in CD34+ CML cells which were refractory to imatinib. Through transcriptome analysis and followed by molecular validation, we further showed that apoptosis induced by fenretinide in CD34+ CML cells was mediated by complex mechanisms of stress responses, probably triggered by elevated levels of intracellular reactive oxygen species. Thus, fenretinide combines with imatinib may represent a new strategy for the treatment of CML, in which fenretinide targets primitive CD34+ CML cells whereas imatinib targets leukemic blasts. This strategy may eventually reduce the risk of relapse and probably resistant as well in CML patients.

2009-12-01 | GSE17480 | GEO

Gene expression profiling of pre-HPCs derived from CML-iPSCs

Project description:Properties of cancer stem cells (CSC) involved in drug-resistance and relapse have significant effect on clinical outcome. Although tyrosine kinase inhibitors (TKIs) have dramatically improved survival of patients with chronic myelogenous leukemia (CML), TKIs have not fully cure CML due to TKI-resistant CML stem cells. Moreover, the relapse after discontinuation of TKIs has not been predicted in CML patients with best TKI-response. In our study, pre-hematoopoietic progenitor cells (pre-HPCs), a model of CML stem cells derived from CML-iPSCs identified a novel antigen of TKI-resistant CML cells. Even in the fraction reported as TKI-sensitive, the antigen+ cells showed TKI-resistance in CML patients. In addition, residual CML cells in patients with optimal TKI-response were concentrated in the antigen+ population.

2016-12-21 | GSE92624 | GEO

Adaptive Metabolic Response to Tyrosine Kinase Inhibition in Chronic Myelogenous Leukemia Stem Cells

Project description:Tyrosine kinase inhibitors (TKI) are highly effective in treating chronic myelogenous leukemia (CML), but primitive, quiescent CML stem cells persist as a source for recurrence. The effects of TKI treatment on CML stem cell metabolism, and the role of metabolic reprogramming in CML stem cell persistence after TKI treatment are not clear. Here we show that TKI treatment in a CML mouse model leads to acute inhibition of aerobic glycolysis, glutaminolysis, TCA cycle and oxidative phosphorylation (OXPHOS) in CML progenitor cells, but that these pathways are restored with continued TKI treatment. Single cell analysis reveals that primitive CML stem cell subpopulations characterized by lower OXPHOS, glycolysis, nucleotide metabolism, and MYC gene signatures are enriched after TKI treatment. TKI treatment initially results in broad inhibition of energy metabolism gene signatures, but continued treatment leads to metabolic reprogramming in persistent stem cells, with enhanced OXPHOS and MYC gene signatures. TKI treatment enhanced HIF-1 activity in quiescent CML stem cells, and addition of a HIF-1 inhibitor significantly depleted CML stem cells in TKI-treated mice. Our results identify mechanisms of metabolic adaptation in CML stem cells following TKI treatment, which can be targeted to deplete persistent quiescent CML stem cells.

2023-08-30 | GSE207346 | GEO

Expression profiling in exosomal miRNAs of CML patients with musculoskeletal pain associated with discontinuation of Imatinib

Project description:An approximately 60% of chronic myeloid leukemia (CML) patients who achieved a deep molecular response for more than 2 years maintained a major molecular response after discontinuation of imatinib. These findings indicate the possibility that a portion of CML patients treated with Tyrosine kinase inhibitors (TKIs) could discontinue TKI therapy, although long-term prognosis and/or adverse events after TKIs cessation remain unclear. Recent reports showed that transient musculoskeletal pain occurs in approximately 30% of CML patients after stopping imatinib. To ascertain the factors underlying musculoskeletal events after TKI cessation, we investigated exosomal miRNA in five CML patients who did not experience musculoskeletal events and five patients with musculoskeletal pain after stopping TKIs.

2016-12-15 | GSE85903 | GEO

Transcription profiling of human untreated and fenretinide-treated CD34+ cells from 4 CML patients

Project description:Imatinib therapy is first-line treatment for chronic myeloid leukemia (CML), and its failure to target CML progenitor/stem cells may lead to an increased risk of relapse. We report here that fenretinide, a well-tolerated vitamin A derivative, is capable of eradicating primitive CML progenitor/stem cells and significantly enhances the efficacy of imatinib at physiologically achievable concentrations. As tested by colony forming cell assays, formation of various colonies derived primitive CML CD34+ cells was significantly suppressed by fenretinide, particularly with respect to the formation of colonies derived from erythroid progenitors and more primitive CML progenitor/stem cells. Also, fenretinide significantly enhanced the ability of imatinib to suppress the formation of the colonies. Moreover, fenretinide was able to induce apoptosis in primitive CML CD34+ cells while sparing the normal counterparts. In particular, primitive CML CD34+CD38- cells appeared to be most sensitive to fenretinide induced apoptosis. Through transcriptome analysis and molecular validation, we further showed that fenretinide induced apoptosis in CML CD34+ cells was probably mediated by a series of stress responsive events which were likely triggered by elevated levels of intracellular reactive oxygen species. Accordingly, the combination of fenretinide and imatinib may provide a potential solution for overcoming relapse and resistance in CML. Experiment Overall Design: Transcriptome profiles of CML CD34+ cells with and without fenretinide treatment were analyzed using whole genome expression arrays (Affymetrix HG-U133 Plus 2.0) in four CML patients (CML32, CML33, CML34 and CML35, see Table 1). To minimize potential data biases, both treated and untreated cell samples were maintained in culture for 48 hours before hybridization.

2009-12-05 | E-GEOD-17480 | biostudies-arrayexpress

Targeting Integrated Stress Response by ISRIB combined with Imatinib attenuates STAT5 signaling and eradicates therapy-resistant Chronic Myeloid Leukemia cells

Project description:Integrated Stress Response (ISR) facilitates cellular adaptation to a variable environmental conditions by reprogramming cellular response. Activation of ISR was reported in neurological disorders and solid tumours, but its function in hematological malignancies remains largely unknown. Previously we showed that ISR is activated in chronic myeloid leukemia (CML) CD34+ cells, and its activity correlates with disease progression and imatinib resistance. Here we demonstrate that inhibition of ISR by small molecule ISRIB, but not by PERK inhibitor GSK2656157, restores sensitivity to imatinib and eliminates CML-BP CD34+ resistant cells. We found that In PDX mouse model bearing CD34+ imatinib/dasatinib-resistant CML blasts with PTPN11 gain-of-function mutation, combination of imatinib and ISRIB decreases leukemia engraftment. Furthermore, genes related to SGK3, RAS/RAF/MAPK, JAK2 and IFN pathways were downregulated upon combined treatment. Remarkably, we confirmed that ISRIB and imatinib combination decreases STAT5 phosphorylation and inhibits expression of STAT5-target genes responsible for proliferation, viability and stress response. Thus, our data point to a substantial effect of imatinib and ISRIB combination, that results in transcriptomic deregulation and eradication of imatinib-resistant cells. Our findings suggest such drug combination might improve therapeutic outcome of TKI-resistant leukemia patients exhibiting constitutive STAT5 activation.

2022-11-04 | GSE171853 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data