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MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia

Nucleoside analog, cytarabine (ara-C) is the mainstay of acute myeloid leukemia (AML) chemotherapy. Cytarabine and other nucleoside analogs require activation to the triphosphate form (ara-CTP). Intracellular ara-CTP levels demonstrate significant inter-patient variation and have been related to the...

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Autores principales: Bhise, Neha S., Elsayed, Abdelrahman H., Cao, Xueyuan, Pounds, Stanley, Lamba, Jatinder K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523677/
https://www.ncbi.nlm.nih.gov/pubmed/31022985
http://dx.doi.org/10.3390/genes10040319
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author Bhise, Neha S.
Elsayed, Abdelrahman H.
Cao, Xueyuan
Pounds, Stanley
Lamba, Jatinder K.
author_facet Bhise, Neha S.
Elsayed, Abdelrahman H.
Cao, Xueyuan
Pounds, Stanley
Lamba, Jatinder K.
author_sort Bhise, Neha S.
collection PubMed
description Nucleoside analog, cytarabine (ara-C) is the mainstay of acute myeloid leukemia (AML) chemotherapy. Cytarabine and other nucleoside analogs require activation to the triphosphate form (ara-CTP). Intracellular ara-CTP levels demonstrate significant inter-patient variation and have been related to therapeutic response in AML patients. Inter-patient variation in expression levels of drug transporters or enzymes involved in the activation or inactivation of cytarabine and other analogs is a prime mechanism contributing to development of drug resistance. Since microRNAs (miRNAs) are known to regulate gene-expression, the aim of this study was to identify miRNAs involved in regulation of messenger RNA expression levels of cytarabine pathway genes. We evaluated miRNA and gene-expression levels of cytarabine metabolic pathway genes in 8 AML cell lines and The Cancer Genome Atlas (TCGA) data base. Using correlation analysis and functional validation experiments, our data demonstrates that miR-34a-5p and miR-24-3p regulate DCK, an enzyme involved in activation of cytarabine and DCTD, an enzyme involved in metabolic inactivation of cytarabine expression, respectively. Further our results from gel shift assays confirmed binding of these mRNA-miRNA pairs. Our results show miRNA mediated regulation of gene expression levels of nucleoside metabolic pathway genes can impact interindividual variation in expression levels which in turn may influence treatment outcomes.
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spelling pubmed-65236772019-06-03 MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia Bhise, Neha S. Elsayed, Abdelrahman H. Cao, Xueyuan Pounds, Stanley Lamba, Jatinder K. Genes (Basel) Article Nucleoside analog, cytarabine (ara-C) is the mainstay of acute myeloid leukemia (AML) chemotherapy. Cytarabine and other nucleoside analogs require activation to the triphosphate form (ara-CTP). Intracellular ara-CTP levels demonstrate significant inter-patient variation and have been related to therapeutic response in AML patients. Inter-patient variation in expression levels of drug transporters or enzymes involved in the activation or inactivation of cytarabine and other analogs is a prime mechanism contributing to development of drug resistance. Since microRNAs (miRNAs) are known to regulate gene-expression, the aim of this study was to identify miRNAs involved in regulation of messenger RNA expression levels of cytarabine pathway genes. We evaluated miRNA and gene-expression levels of cytarabine metabolic pathway genes in 8 AML cell lines and The Cancer Genome Atlas (TCGA) data base. Using correlation analysis and functional validation experiments, our data demonstrates that miR-34a-5p and miR-24-3p regulate DCK, an enzyme involved in activation of cytarabine and DCTD, an enzyme involved in metabolic inactivation of cytarabine expression, respectively. Further our results from gel shift assays confirmed binding of these mRNA-miRNA pairs. Our results show miRNA mediated regulation of gene expression levels of nucleoside metabolic pathway genes can impact interindividual variation in expression levels which in turn may influence treatment outcomes. MDPI 2019-04-24 /pmc/articles/PMC6523677/ /pubmed/31022985 http://dx.doi.org/10.3390/genes10040319 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Bhise, Neha S.
Elsayed, Abdelrahman H.
Cao, Xueyuan
Pounds, Stanley
Lamba, Jatinder K.
MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
title MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
title_full MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
title_fullStr MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
title_full_unstemmed MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
title_short MicroRNAs Mediated Regulation of Expression of Nucleoside Analog Pathway Genes in Acute Myeloid Leukemia
title_sort micrornas mediated regulation of expression of nucleoside analog pathway genes in acute myeloid leukemia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523677/
https://www.ncbi.nlm.nih.gov/pubmed/31022985
http://dx.doi.org/10.3390/genes10040319
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