The lncRNA expression profile signature of leukemia stem cells is altered upon PI3K/mTOR inhibition: an in vitro and in silico study

Abstract

Genetic and/or epigenetic alterations in hematopoietic stem cells (HSCs) contribute to leukemia stem cell (LSC) formation. We aimed to identify alterations in the lncRNA expression profile signature of LSCs upon inhibition of PI3K/Akt/mTOR signaling, which provides selective advantages to LSCs. We also aimed to elucidate the potential interaction networks and functions of differentially expressed lncRNAs (DELs). We suppressed PI3K/Akt/mTOR signaling in LSC and HSC cell-lines by specific PI3K/mTOR dual-inhibitor (VS-5584) and confirmed the inhibition by antibody-array. We defined DELs by qRT-PCR. Increased SRA, ZEB2-AS1, antiPeg11, DLX6-AS, SNHG4, and decreased H19, PCGEM1, CAR-Intergenic-10, L1PA16, IGF2AS, and SNHG5 levels (|log2fold-change|>5) were strictly associated with PI3K/Akt/mTOR pathway inhibition in LSC. We performed in silico analyses for DELs. ZEB2-AS1 was found to be specifically expressed in normal bone marrow and predominantly lower in leukemic cell-lines. Three sub-clusters were identified for DELs and they were associated with “abnormality of multiple cell lineages in the bone marrow.” DELs were most highly enriched for “glucuronidation” Reactome pathway and “ascorbate and aldarate metabolism” and “inositol phosphate metabolism” KEGG pathways. Transcription factors, MBD4, NANOG, PAX6, RELA, CEBPB, and CEBPA were predicted to be associated with the DEL profile. SRA was predicted to interact with CREB1, RARA, and PPARA. The possible DELs’ targets were predicted to form six ontological groups, be highly enriched for phosphoprotein, and be involved in “PPAR signaling pathway” and “ChREBP regulation by carbohydrates and cAMP.” These results will help to elucidate the roles of lncRNAs in the mechanisms that provide selective advantages to leukemia stem cells.

Keywords:

• lncRNA
• PI3K/Akt/mTOR pathway
• leukemia stem cell
• hematopoietic stem cell
• ın vitro
• ın silico

Acknowledgments

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author’ contributions

Both authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Cagla Kayabasi. The first draft of the manuscript was written by Cagla Kayabasi. Supervision, review and editing were done by Cumhur Gunduz.

Disclosure statement

The authors report no conflict of interest.

Ethics approval and consent to participate

The local ethics committee ruled that no formal ethics approval was required in this particular case.

Consent for publication

None.

Data availability statement

The data are available from the corresponding author upon reasonable request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.