Targeting the LncRNA DUXAP8/miR-29a/ Network Restores Doxorubicin Chemosensitivity PI3K-AKT-mTOR Signaling and Synergizes With Inotuzumab Ozogamicin in Chemotherapy-Resistant B-Cell Acute Lymphoblastic Leukemia

Overview

Journal Front Oncol

Specialty Oncology

Date 2022 Mar 21

PMID 35311115

Authors

Li Zhang

Shixia Zhou

Tiejun Zhou

Xiaoming Li

Junling Tang

Affiliations

Soon will be listed here.

Abstract

Purpose: This study aimed to determine the expression profiles of long non-coding RNA (lncRNA), microRNA (miRNA), and mRNA in chemotherapy-resistant B-cell acute lymphoblastic leukemia (B-ALL).

Methods: LncRNA, miRNA, and mRNA profiles were assessed by RNA-seq in diagnostic bone marrow samples from 6 chemotherapy-resistant and 6 chemotherapy-sensitive B-ALL patients. The lncRNA DUXAP8/miR-29a/ signaling network was identified as the most dysregulated in chemoresistant patient samples, and its effect on cellular phenotypes, PI3K-AKT-mTOR signaling, and chemosensitivity of doxorubicin (Dox)-resistant Nalm-6 (N6/ADR), and Dox-resistant 697 (697/ADR) cells were assessed. Furthermore, its synergy with inotuzumab ozogamicin treatment was investigated.

Results: 1,338 lncRNAs, 75 miRNAs, and 1620 mRNAs were found to be dysregulated in chemotherapy-resistant B-ALL in comparison to chemotherapy-sensitive B-ALL patient samples. Through bioinformatics analyses and RT-qPCR validation, the lncRNA DUXAP8/miR-29a/ network and PI3K-AKT-mTOR signaling were identified as significantly associated with B-ALL chemotherapy resistance. In N6/ADR and 697/ADR cells, LncRNA DUXAP8 overexpression and overexpression induced proliferation and inhibited apoptosis, and their respective knockdowns inhibited proliferation, facilitated apoptosis, and restored Dox chemosensitivity. MiR-29a was shown to affect the lncRNA DUXAP8/ network, and luciferase reporter gene assay showed direct binding between lncRNA DUXAP8 and miR-29a, as well as between miR-29a and . Targeting lncRNA DUXAP8/miR-29a/ network synergized with inotuzumab ozogamicin's effect on N6/ADR and 697/ADR cells.

Conclusion: Targeting the lncRNA DUXAP8/miR-29a/ network not only induced an apoptotic effect on Dox-resistant B-ALL and restored Dox chemosensitivity PI3K-AKT-mTOR signaling but also showed synergism with inotuzumab ozogamicin treatment.

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