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MiR-10a as a therapeutic target and predictive biomarker for MDM2 inhibition in acute myeloid leukemia.

ABSTRACT: Pharmacological inhibition of MDM2/4, which activates the critical tumor suppressor p53, has been gaining increasing interest as a strategy for the treatment of acute myeloid leukemia (AML). While clinical trials of MDM2 inhibitors have shown promise, responses have been confined to largely molecularly undefined patients, indicating that new biomarkers and optimized treatment strategies are needed. We previously reported that the microRNA miR-10a is strongly overexpressed in some AML, and demonstrate here that it modulates several key members of the p53/Rb network, including p53 regulator MDM4, Rb regulator RB1CC1, p21 regulator TFAP2C, and p53 itself. The expression of both miR-10a and its downstream targets were strongly predictive of MDM2 inhibitor sensitivity in cell lines, primary AML specimens, and correlated to response in patients treated with both MDM2 inhibitors and cytarabine. Furthermore, miR-10a inhibition induced synergy between MDM2 inhibitor Nutlin-3a and cytarabine in both in vitro and in vivo AML models. Mechanistically this synergism primarily occurs via the p53-mediated activation of cytotoxic apoptosis at the expense of cytoprotective autophagy. Together these findings demonstrate that miR-10a may be useful as both a biomarker to identify patients most likely to respond to cytarabine+MDM2 inhibition and also a druggable target to increase their efficacy.

SUBMITTER: Vu TT

PROVIDER: S-EPMC8257503 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BACKGROUND: Chronic Myeloid Leukemia (CML) is a malignant pluripotent stem cells disorder of myeloid cells. In CML patients, polymorphonuclear leukocytes (PMNL) the terminally differentiated cells of myeloid series exhibit defects in several actin dependent functions such as adhesion, motility, chemotaxis, agglutination, phagocytosis and microbicidal activities. A definite and global abnormality was observed in stimulation of actin polymerization in CML PMNL. Signalling molecules ras and rhoGTPases regulate spatial and temporal polymerization of actin and thus, a broad range of physiological processes. Therefore, status of these GTPases as well as actin was studied in resting and fMLP stimulated normal and CML PMNL. METHODS: To study expression of GTPases and actin, Western blotting and flow cytometry analysis were done, while spatial expression and colocalization of these proteins were studied by using laser confocal microscopy. To study effect of inhibitors on cell proliferation CCK-8 assay was done. Significance of differences in expression of proteins within the samples and between normal and CML was tested by using Wilcoxon signed rank test and Mann-Whitney test, respectively. Bivariate and partial correlation analyses were done to study relationship between all the parameters. RESULTS: In CML PMNL, actin expression and its architecture were altered and stimulation of actin polymerization was absent. Differences were also observed in expression, organization or stimulation of all the three GTPases in normal and CML PMNL. In normal PMNL, ras was the critical GTPase regulating expression of rhoGTPases and actin and actin polymerization. But in CML PMNL, rhoA took a central place. In accordance with these, treatment with rho/ROCK pathway inhibitors resulted in specific growth inhibition of CML cell lines. CONCLUSIONS: RhoA has emerged as the key molecule responsible for functional defects in CML PMNL and therefore can be used as a therapeutic target in CML.

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MiR-10a as a therapeutic target and predictive biomarker for MDM2 inhibition in acute myeloid leukemia.

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