Abstract
PurposeThis 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).MethodsLncRNA, 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/PIK3CA 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.Results1,338 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/PIK3CA 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 PIK3CA 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/PIK3CA network, and luciferase reporter gene assay showed direct binding between lncRNA DUXAP8 and miR-29a, as well as between miR-29a and PIK3CA. Targeting lncRNA DUXAP8/miR-29a/PIK3CA network synergized with inotuzumab ozogamicin’s effect on N6/ADR and 697/ADR cells.ConclusionTargeting the lncRNA DUXAP8/miR-29a/PIK3CA network not only induced an apoptotic effect on Dox-resistant B-ALL and restored Dox chemosensitivity via PI3K-AKT-mTOR signaling but also showed synergism with inotuzumab ozogamicin treatment.
Highlights
Acute lymphoblastic leukemia (ALL), as a hematological malignancy with the unrestricted proliferation of abnormal, immature lymphocytes or their progenitors that cause bone marrow element dysregulation, affects 1.7 new cases per 100,000 populations annually and accounts for nearly 2% of all lymphoid neoplasms in the United States [1, 2]
Of 12 bone marrow samples, 6 samples were from the adult B-cell ALL (B-ALL) patients who achieved complete remission (CR) following the induction therapy with the VDP regimen, and these patients were considered as chemotherapy-sensitive patients (S-ALL) in the study; another 6 samples were from the adult B-ALL patients failing to achieve response at the end of the induction therapy with the VDP regimen, who exhibited a minimal residual disease (MRD) >1 × 10-2 by flow cytometry at the end of the induction therapy, and these patients were considered as chemotherapy-resistant patients (R-ALL) in the study
Experiments were performed via modifying Long non-coding RNA (lncRNA) DUXAP8, miR-29a, and PIK3CA to explore their effect on Dox-resistant B-ALL cell proliferation, apoptosis, Dox chemosensitivity, etc
Summary
Acute lymphoblastic leukemia (ALL), as a hematological malignancy with the unrestricted proliferation of abnormal, immature lymphocytes or their progenitors that cause bone marrow element dysregulation, affects 1.7 new cases per 100,000 populations annually and accounts for nearly 2% of all lymphoid neoplasms in the United States [1, 2]. Long-term survival benefits are only achieved in the majority of childhood ALL, while only 30%–40% of adult ALL achieves long-term disease-free survival; especially, after relapse or refractoriness, the role of salvage chemotherapy is very limited, with less than 10% of long survival [7, 8]. Long non-coding RNA (lncRNA), a kind of non-coding RNA recognized recently with a length of more than 200 bp, has been reported to regulate a huge amount of biological processes and to be involved in the pathogenesis of most diseases via its interaction with cellular compounds such as miRNA, mRNA, DNA, and proteins [9–13]. The function of a large majority of lncRNAs in B-ALL remains obscure, and in particular, seldom studies have investigated the comprehensive lncRNA profile involved in treatment refractoriness, not to mention the detailed molecule mechanism of some key lncRNAs underlying chemotherapy resistance
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