Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia

Hatzl, Stefan; Perfler, Bianca; Wurm, Sonja; Uhl, Barbara; Quehenberger, Franz; Ebner, Susanne; Troppmair, Jakob; Reinisch, Andreas; Wölfler, Albert; Sill, Heinz; Zebisch, Armin

doi:10.3390/cancers12020496

Cited by 14 publications

(11 citation statements)

References 65 publications

(134 reference statements)

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“…Although novel targeted treatment approaches have been developed for patients with AML, their prognosis is still dismal with 5-year-survival rates of 40%-45% in patients below the age of 65 years and less than 20% in patients aged 65 years or older [7,15]. Relapsed disease as a consequence of diverse molecular aberrations affecting dormant LSCs is the main reason for this dismal outcome [16][17][18][19][20]. In AML, parameters influencing treatment decisions as well as outcome include both patient-specific characteristics and leukemia-specific aberrations.…”

Section: Introductionmentioning

confidence: 99%

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Dutta

Pregartner

Rücker

et al. 2020

Cancers

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Mutations of the TP53 gene occur in a subset of patients with acute myeloid leukemia (AML) and confer an exceedingly adverse prognosis. However, whether different types of TP53 mutations exert a uniformly poor outcome has not been investigated yet. Here, we addressed this issue by analyzing data of 1537 patients intensively treated within protocols of the German-Austrian AML study group. We classified TP53 mutations depending on their impact on protein structure and according to the evolutionary action (EAp53) score and the relative fitness score (RFS). In 98/1537 (6.4%) patients, 108 TP53 mutations were detected. While the discrimination depending on the protein structure and the EAp53 score did not show a survival difference, patients with low-risk and high-risk AML-specific RFS showed a different overall survival (OS; median, 12.9 versus 5.5 months, p = 0.017) and event-free survival (EFS; median, 7.3 versus 5.2 months, p = 0.054). In multivariable analyses adjusting for age, gender, white blood cell count, cytogenetic risk, type of AML, and TP53 variant allele frequency, these differences were statistically significant for both OS (HR, 2.14; 95% CI, 1.15–4.0; p = 0.017) and EFS (HR, 1.97; 95% CI, 1.06–3.69; p = 0.033). We conclude that the AML-specific RFS is of prognostic value in patients with TP53-mutated AML and a useful tool for therapeutic decision-making.

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Section: Introductionmentioning

confidence: 99%

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Dutta

Pregartner

Rücker

et al. 2020

Cancers

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“…Jiang Y et al found that the proliferation of hepatocellular carcinoma cells is promoted by the miR-23a-Stat5A-Akt signaling pathway[ 22 ]. Consistent with solid tumor studies, miR-23a has been reported to mediate cytarabine resistance in AML cells by targeting the TOP2B gene and to correlate with the relapsed/refractory stage[ 23 ]. However, other authors have validated that miR-23a is involved in the inhibition of tumor cell proliferation.…”

Section: Discussionmentioning

confidence: 66%

Restoration of miR-23a expression by chidamide sensitizes CML cells to imatinib treatment with concomitant downregulation of CRYAB

et al. 2022

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MicroRNAs (miRNAs) are involved in various processes from the initiation and development of cancers, including chronic myeloid leukemia (CML). In this report, we aimed to investigate the roles of miR-23a in the regulation of imatinib mesylate (IM) sensitivity in CML cells and the possible mechanisms involved in this process. We demonstrated that the expression of miR-23a was markedly low in bone marrow mononuclear cells from patients in whom IM treatment had failed and imatinib-resistant K562/G01 cells when compared to patients with optimal responses and imatinib-sensitive K562 cells, respectively. Overexpression of miR-23a was shown to induce apoptosis of K562/G01 cells and sensitize these cells to imatinib treatment. With the aid of bioinformatics analysis, we revealed that CRYAB could be a potential downstream effector of miR-23a, contributing to miR-23a-mediated IM resistance. We also observed that the expression of CRYAB was inversely correlated with miR-23a expression in CML cell lines and patient samples. Importantly, chidamide upregulated miR-23a expression and reversed the IM resistance of CML cells. Together, these findings strongly suggest that miR-23a acts as a tumor suppressor by downregulating CRYAB expression. Restoration of miR-23a by chidamide may therefore have a therapeutic effect in controlling the sensitivity of CML cells to imatinib.

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“…Furthermore, we found that overexpressed MEG3 could promote the sensitivity of AML cells to AraC. AraC is the key element of all cytostatic AML treatments [ 29 ]. The theoretical basis for AraC therapy was developed in the 1970s and has since been utilized in AML treatment [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor-suppressive MEG3 induces microRNA-493-5p expression to reduce arabinocytosine chemoresistance of acute myeloid leukemia cells by downregulating the METTL3/MYC axis

et al. 2022

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Background Chemoresistance serves as a huge obstacle for acute myeloid leukemia (AML) patients. To counteract the chemoresistance in AML cells, we discussed the role of maternally expressed gene 3 (MEG3) in arabinocytosine (AraC) chemoresistance in AML cells. Methods MEG3, microRNA (miR)-493-5p, methyltransferase-like 3 (METTL3) and MYC expression in AML cells was determined and then their interactions were also analyzed. Then, the viability and apoptosis of AML cells were determined through loss- and gain- function assay. The level of m6A modification in AML cells was examined. AML mouse models were also established to validate the potential roles of MEG3. Results MEG3 and miR-493-5p were downregulated in AML cells, and they were lower in resistant cells than in parental cells. MEG3 led to elevated expression of miR-493-5p which targeted METTL3. METTL3 increased expression of MYC by promoting its m6A levels. Overexpression of MEG3 and miR-493-5p or knockdown of METTL3 inhibited HL-60 and Molm13 cell proliferation and promoted their apoptosis. Overexpressed MEG3 induced heightened sensitivity of AML cells to AraC. However, the suppression of miR-493-5p reversed the effects of overexpressed MEG3 on AML cells. Conclusions Collectively, MEG3 could upregulate miR-493-5p expression and suppress the METTL3/MYC axis through MYC m6A methylation, by which MEG3 promoted the chemosensitivity of AML cells.

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Increased Expression of Micro-RNA-23a Mediates Chemoresistance to Cytarabine in Acute Myeloid Leukemia

Cited by 14 publications

References 65 publications

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Functional Classification of TP53 Mutations in Acute Myeloid Leukemia

Restoration of miR-23a expression by chidamide sensitizes CML cells to imatinib treatment with concomitant downregulation of CRYAB

Tumor-suppressive MEG3 induces microRNA-493-5p expression to reduce arabinocytosine chemoresistance of acute myeloid leukemia cells by downregulating the METTL3/MYC axis

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