MicroRNA signature refine response prediction in CML

Alves, Raquel; Gonçalves, Ana Cristina; Jorge, Joana; Marques, Gilberto; Luís, Dino; Ribeiro, André; Freitas-Tavares, Paulo; Oliveiros, Bárbara; Almeida, António; Sarmento‐Ribeiro, Ana Bela

doi:10.1038/s41598-019-46132-9

Cited by 27 publications

(28 citation statements)

References 38 publications

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“…However, by our approach we were able to identify miR-142-5p as most robustly expressed miRNA showing significant expression differences in both, peripheral blood and bone marrow samples. Although the expression differences were modest, they could substantially influence cellular processes [74]. This is also supported by the recent study of Alves et al in CML patients, which described slight miRNA expression differences between TKI non-responders and responders at diagnosis that became more pronounced after six and twelve months of therapy [75].…”

Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

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Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance

et al. 2020

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Background Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm characterized by constitutive activity of the tyrosine kinase BCR-ABL1. Although the introduction of tyrosine kinase inhibitors (TKIs) has substantially improved patients’ prognosis, drug resistance remains one of the major challenges in CML therapy. MicroRNAs (miRNAs), a class of short non-coding RNAs acting as post-transcriptional regulators, are implicated in CML progression and drug resistance. The aim of the present study was to analyze the miRNA expression profiles of 45 treatment-naïve CML patients in chronic phase (28 peripheral blood and 17 bone marrow samples) with respect to future response to imatinib therapy. Methods TaqMan low density arrays were used to analyze the miRNA expression pattern of the patient samples. For selected microRNAs, reporter gene assays were performed to study their ability to regulate CML associated target genes. Results Significant lower expression levels of miR-142-5p were identified in both, peripheral blood and bone marrow samples of future non-responders suggesting a potential tumor suppressor role of this miRNA. This was supported by reporter gene assays that identified the survival, proliferation and invasion promoting CML related genes ABL2, cKIT, MCL1 and SRI as targets of miR-142-5p and miR-365a-3p, the latter identified as potential biomarker in peripheral blood samples. Conclusion MiR-142-5p and to a certain extend also miR-365a-3p were able to discriminate treatment-naïve CML patients not responding to imatinib in the course of their treatment from patients, who responded to therapy. However, further large-scale studies should clarify if the identified miRNAs have the potential as predictive biomarkers for TKI resistance.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance

et al. 2020

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“…A few studies point out the involvement of immune cells for the control of TFR. It has been demonstrated that there is an increase in natural killer (NK) cells and a decrease in CD3 + CD8 + CD62L + cells in patients in whom imatinib was discontinued (STOP-IM) compared to CML patients taking imatinib in complete molecular remission (CMR), which was positively associated with CMR [ 124 ]. Another trial (EURO-SKI) revealed a higher rate of TFR in CML patients with a higher percentage of NK, but not B- or T-cells.…”

Section: Treatment Free Remissionmentioning

confidence: 99%

Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

Minciacchi

Kumar

Krause

2021

Cells

100

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Chronic myeloid leukemia (CML) has been a “model disease” with a long history. Beginning with the first discovery of leukemia and the description of the Philadelphia Chromosome and ending with the current goal of achieving treatment-free remission after targeted therapies, we describe here the journey of CML, focusing on molecular pathways relating to signaling, metabolism and the bone marrow microenvironment. We highlight current strategies for combination therapies aimed at eradicating the CML stem cell; hopefully the final destination of this long voyage.

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“…However, the relevance between miR-21 and TKI resistance in CML has rarely been reported. In a study that predicted which patients would achieve the optimal response with TKIs, miR-21 expression levels were found to be the highest in patients who did not respond optimaliy after 6 and 12 months of treatment [23]. In this case, miR-21 may be a novel therapeutic strategy to reverse TKIs resistance in…”

Section: Introductionmentioning

confidence: 95%

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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MicroRNA signature refine response prediction in CML

Cited by 27 publications

References 38 publications

Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance

Expression differences of miR-142-5p between treatment-naïve chronic myeloid leukemia patients responding and non-responding to imatinib therapy suggest a link to oncogenic ABL2, SRI, cKIT and MCL1 signaling pathways critical for development of therapy resistance

Chronic Myeloid Leukemia: A Model Disease of the Past, Present and Future

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

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