A tyrosine kinase-STAT5-miR21-PDCD4 regulatory axis in chronic and acute myeloid leukemia cells

Espadinha, Anne-Sophie; Prouzet‐Mauléon, Valérie; Claverol, Stéphane; Lagarde, Valérie; Bonneu, Marc; Mahon, François‐Xavier; Cardinaud, Bruno

doi:10.18632/oncotarget.19192

Cited by 21 publications

(19 citation statements)

References 39 publications

(59 reference statements)

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“…2b). This was consistent with previous studies that have shown increased expression of HBZ in imatinibtreated cells 14,15 . Differentially expressed genes (DEGs) between the two transition states were also identified ( Supplementary Fig.…”

supporting

confidence: 94%

Multiplexed single-cell RNA-seq via transient barcoding for drug screening

Shin

Lee

et al. 2018

Preprint

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To simultaneously analyze multiple samples of various conditions with scRNA-seq, we developed a universal sample barcoding method through transient transfection of SBOs. A 48-plex drug treatment experiment of pooled samples analyzed by a single run of Drop-Seq revealed a unique transcriptome response for each drug and target-specific gene expression signatures at the single-cell level. Our cost-effective method is widely applicable for single-cell profiling of multiple experimental conditions.

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supporting

confidence: 94%

Multiplexed single-cell RNA-seq via transient barcoding for drug screening

Shin

Lee

et al. 2018

Preprint

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“…Internal tandem duplication of receptor-type tyrosine-protein kinase FLT3 (FLT3) and partial tandem duplication of lysine methyltransferase 2A (MLL) are the most common mutations in AML (with frequencies of 30-45% and 5-10%, respectively, in CN-AML), and are associated with poor therapeutic outcomes (20,21). Specifically, lymphoid-specific helicase and enhancer of polycomb homolog 1 were associated with epigenetic regulation in hematopoiesis (22), ring finger protein, LIM domain interacting (RLIM) was associated with the ubiquitylation of AML1-ETO and protein PML-retinoic acid receptor α (23), and programmed cell death 4 was associated with related signaling pathway (24) in myeloid leukemia. MLL (KMT2A) was associated with fusions and acute leukemia (25), and La ribonucleoprotein domain family member 4B (26), jumonji domain containing 1C (JMJD1C) (27) and SYNCRIP (28) (35).…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, unsupervised clustering was performed with scRNA-seq data from patient B using the SC3 pipeline (version 1.12.0) (19). The functions of DGEs were determined through a literature review (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)…”

Section: Gene Fusion Predictionmentioning

confidence: 99%

Single‑cell RNA sequencing of t(8;21) acute myeloid leukemia for risk prediction

Xiong

Huang

et al. 2020

Oncol Rep

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Single-cell RNA sequencing (scRNA-seq) of bone marrow or peripheral blood samples from patients with acute myeloid leukemia (AML) enables the characterization of heterogeneous malignant cells. A total of 87 cells from two patients with t(8;21) AML were analyzed using scRNA-seq. Clustering methods were used to separate leukemia cells into different sub-populations, and the expression patterns of specific marker genes were used to annotate these populations. Among the 31 differentially expressed genes in the cells of a patient who relapsed after hematopoietic stem cell transplantation, 13 genes were identified to be associated with leukemia. Furthermore, three genes, namely AT-rich interaction domain 2, lysine methyltransferase 2A and synaptotagmin binding cytoplasmic RNA interacting protein were validated as possible prognostic biomarkers using two bulk expression datasets. Taking advantage of scRNA-seq, the results of the present study may provide clinicians with several possible biomarkers to predict the prognostic outcomes of t(8;21) AML.

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“…Espadinha et al used microarray-based miRNA expression profiling in CML model K562 cells and found that oncoprotein BCR-ABL1 is dependent on the presence of two STAT binding sites on the miR-21 promoter and the phosphorylation of STAT5 to regulate the expression of miR-21 [43]. Wang et al found that emodin showed anti-tumor activity in vivo and in vitro by inactivating PTEN/PI3KAKT and deleting BCR-ABL to induce apoptosis [44].…”

Section: Discussionmentioning

confidence: 99%

CRISPR/Cas9-mediated microRNA-21 Cleavage Sensitizes the Treatment Response to Dasatinib in Chronic Myeloid Leukemia Cell Line K562

Zhang¹,

Wang²,

Li³

et al. 2020

Preprint

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Background: Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1 kinase are effective in treating chronic myeloid leukemia (CML), but TKI resistance occurs in a significant number of patients, and the underlying molecular mechanisms of this resistance remain largely unknown. As an oncomiR, microRNA-21(miR-21) functions directly in drug resistance, but its relationship with TKI resistance in CML is rarely reported. As a novel and effective gene editing tool, clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 9(CRISPR/Cas9) has certain advantages in completely knocking out target genes at the gene level. Methods: We successfully constructed lentiviruses LV-VMP1-sgRNA (045001) and human chronic myeloid leukemia K562 cells were transducted with them. Single-cell-derived clones were screened for miR-21 deletion by genomic DNA PCR and Sanger sequence. RQ-PCR assays was used to confirm the knockout of miR-21. 3-(4,5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide(MTT) and colony formation assays were applied to assess the cell growth inhibition. Imatinib and dasatinib sensitivity was determined by MTT assay and Annexin-V APC/7-AAD double staining flow cytometry. Western blot assay was performed to measure the levels of Phosphatase and tensin homolog(PTEN), Phosphatidylinositol 3-kinase(PI3K), Serine/threonine Kinase(AKT), p-AKT, BCR-ABL(P210), p-BCR-ABL (p-P210) . Result: miR-21 knockout inhibited proliferation of K562 cells, promoted their apoptosis and increased their sensitivity to dasatinib. Further mechanism studies suggest that this is achieved by inhibiting the PI3K/AKT signaling pathway and destroying BCR-ABL. Conclusions: Our study reveals the efficacy of CRISPR/Cas9 gene editing to miR-21 in K562 and indicates miR-21 as a potential target in sensitizing dasatinib treatment for CML patients with pool response to the TKI targeting therapy.

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A tyrosine kinase-STAT5-miR21-PDCD4 regulatory axis in chronic and acute myeloid leukemia cells

Cited by 21 publications

References 39 publications

Multiplexed single-cell RNA-seq via transient barcoding for drug screening

Multiplexed single-cell RNA-seq via transient barcoding for drug screening

Single‑cell RNA sequencing of t(8;21) acute myeloid leukemia for risk prediction

CRISPR/Cas9-mediated microRNA-21 Cleavage Sensitizes the Treatment Response to Dasatinib in Chronic Myeloid Leukemia Cell Line K562

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