Induction of a timed metabolic collapse to overcome cancer chemoresistance
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE139159 | GEO | 2020/08/05
REPOSITORIES: GEO
Similar Datasets
Project description: Not available
| S-EPMC8397232 | biostudies-literature
Project description:A genome-wide CRISPR knockout screen investigating resistance to doxorubicin and cytarabine (Dox/AraC) in human AML cell lines identified gene knockout of cyclin dependent kinase inhibitor 2A (CDKN2A) as contributing to resistance. To investigate the therapeutic potential of upregulating CDKN2A expression using WM-1119 and further elucidate its mechanism of action, we performed RNA-seq on WM-1119- (or vehicle control) treated OCI-AML3 cells with or without CRISPR mediated genetic depletion of CDKN2A.
2022-11-22 | GSE205802 | GEO
Project description:Induction of a timed metabolic collapse to overcome cancer chemoresistance
| PRJNA578674 | ENA
Project description:Dormant chemotherapy-resistant leukemia cells can survive for an extended period before relapse. Nevertheless, the mechanisms underlying the development of chemoresistance in vivo remain unclear. Using intravital bone imaging, we characterized the behavior of murine acute myeloid leukemia (AML) cells (C1498) in the bone marrow before and after chemotherapy with cytarabine. Proliferative C1498 cells exhibited high motility in the bone marrow. Cytarabine treatment impaired the motility of residual C1498 cells. However, C1498 cells regained their migration potential after relapse. RNA sequencing revealed that cytarabine treatment promoted MRTF-SRF pathway activation. MRTF inhibition using CCG-203971 augmented the anti-tumor effects of chemotherapy in our AML mouse model, as well as suppressed the migration of chemoresistant C1498 cells. These results provide novel insight into the role of cell migration arrest on the development of chemoresistance in AML, as well as provide a strong rationale for the modulation of cellular motility as a therapeutic target for refractory AML.
2020-07-15 | GSE149853 | GEO
Project description:SIRT3 deacetylase is a critical mitochondrial regulator for mitochondrial metabolism reprogramming and ROS production, and is involved in the regulation of chemoresistance in AML. SIRT3 is a SUMOylated protein, with de-SUMOylation by SENP1, resulted in enhancement of its deacetylase activity. However, the molecular mechanism of de-SUMOylation mediated SIRT3 activation, which may lead to reinforced AML chemoresistance, remains poorly understood. In the current study, we demonstrated that SIRT3 SUMOylation was attenuated by cytarabine, and de-SUMOylation prevented SIRT3 from proteasome degradation. SIRT3 de-SUMOylation was capable of reprogramming mitochondrial biogenesis, and subsequently inhibited mitochondrial ROS production. Furthermore, RNA-seq revealed that expression of a collection of genes was altered by SIRT3 de-SUMOylation, among which the transcription factor HES1, a downstream substrates of Notch1 signaling pathway, was significantly downregulated by SIRT3K288R, the de-SUMOylated and constitutively active mutant of SIRT3. HES1-dependent FAO was inhibited by SIRT3 de-SUMOylation. Moreover, cytarabine synergized with the SENP1 inhibitor momodrin-Ic to eradicate AML blasts in vitro and in xenografts mice models. In summary, the current study revealed a novel role of SIRT3 SUMOylation in regulating chemoresistance in AML via HES1-dependent FAO, which may provide a rationale for SIRT3 SUMOylation-targeted intervention to improve the chemotherapies in AML.
2022-08-17 | GSE179617 | GEO
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
Project description:Acute myeloid leukemia (AML) is characterized by poor clinical outcomes due to high rates of relapse following induction chemotherapy. While many pathogenic drivers have been described in AML, our understanding of the molecular mechanisms mediating chemotherapy resistance remains poor, and initial management of AML continues to rely on standard induction chemotherapy for many patients. Given the importance of identifying new approaches to improve the efficiency of induction therapy in AML, we sought to identify resistance genes to induction therapy in AML and identified ALOX5 is a novel mediator of resistance to anthracycline based therapy. ALOX5 mRNA is expressed at high levels in AML patient blasts in comparison to normal hematopoietic stem/progenitor cells (HSPCs) and ALOX5 mRNA and protein expression is increased in response to induction therapy. Genetic and pharmacologic perturbations of ALOX5 function in vitro and in vivo confirm that ALOX5 positively regulates the leukemogenic potential of AML LSCs, while ALOX5 loss does not significantly affect the function of normal HSPCs. ALOX5 mediates resistance to daunorubicin (DNR) and promotes AML cell survival and maintenance through its leukotriene (LT) synthetic capacity. Specifically, the ALOX5 dependent resistance phenotype depends on its ability to synthesize LTB4 and bind to the LTB receptor (BLTR). Overall, our studies reveal a previously unrecognized role of LT’s in AML pathogenesis and chemoresistance, and provide a potential novel strategy to enhance the therapeutic efficacy of induction chemotherapy in AML.
2022-04-14 | GSE200614 | GEO
Project description:Aberrant secretion of cytokines contributes to pathogenesis of leukemia and is considered a prognostic signature for recurrence of AML. We asked whether molecular targeting of TIFA can perturb NF-κB-dependent secretion of leukemic cytokines and attain better therapeutic efficacy. We performed cytokine antibody array to profile cytokines secreted by U937 cells in response to TIFA dominant-negative fragments and cytarabine treatment.
2016-11-21 | GSE87383 | GEO
Project description:Chemotherapy resistance is the main impediment in the treatment of acute myeloid leukaemia (AML). Despite rapid advances, the various mechanisms that lead to resistance development remain to be defined in detail. Here we report that loss-of-function mutations (LOF) in the histone methyltransferase EZH2 have the potential to confer resistance against the chemotherapeutic agent cytarabine. We identify seven distinct EZH2 mutations leading to loss of H3K27 trimethylation via multiple mechanisms. Analysis of matched diagnosis and relapse samples reveal a heterogenous regulation of EZH2 and a loss of EZH2 in 50% of patients. We confirm that loss of EZH2 induces resistance against cytarabine in the cell lines HEK293T and K562 as well as in a patient-derived xenograft (PDX) model. Proteomics and transcriptomics analysis reveal that resistance is conferred by upregulation of multiple direct and indirect EZH2 target genes that are involved in apoptosis evasion, augmentation of proliferation and alteration of transmembrane transporter function. Our data indicates, that loss of EZH2 results in upregulation of its target genes, providing the cell with a selective growth advantage, which mediates chemotherapy resistance.
2021-03-12 | PXD023139 | Pride
Project description:In acute myeloid leukemias (AML), chemotherapy is frequently followed by disease relapse, yet the mechanism by which AML reemerges is not fully understood. We hypothesized that chemotherapy induces senescence-like dormancy that facilitates survival to genotoxic exposure, allowing AML cells to endure treatment in a transiently dormant state while retaining potential for leukemic repopulation. Here, we show that primary AML cells exhibit hallmark senescence features following treatment with cytarabine (AraC), including growth arrest, increased cellular granularity, senescence-associated-β-galactosidase (SA-β-gal) activity, and senescence-associated transcriptomic alterations. Induction of AraC-induced premature senescence was regulated by the ATR kinase activity and mediated stress-survival. High-throughput single cell RNA (scRNA)-seq analysis of primary AML cells ex vivo and in vivo following chemotherapy suggest active transcriptional programming towards senescent-like dormancy instead of enrichment for leukemia stem cells (LSCs). scRNA-seq of sorted AraC-induced premature senescent AML cells demonstrated a heterogenous population including a fraction of cells with simultaneous expression of dormancy- and senescence-associated gene signatures. Xenotransplantation of AraC-induced premature senescent AML cells into mice demonstrated that senescent-like AML cells maintain leukemia-repopulating potential. Altogether, we propose a mechanism of AML relapse whereby AML cells tolerate chemotherapy via acquisition of a transient senescent-like state.
2021-03-14 | GSE146592 | GEO