MicroRNA-mRNA pairs associated with outcome in AML: From in vitro cell-based studies to AML patients

Neha S. Bhise, Lata Chauhan, Miyoung Shin, Xueyuan Cao, Stanley Pounds, Vishal Lamba, Jatinder K. Lamba

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Cytarabine is the primary chemotherapeutic agent used for treatment of acute myeloid leukemia (AML). Disease relapse after initial remission remains one of the most pressing therapeutic challenges in the treatment of AML. Relapsed disease is often resistant to cytarabine and subsequent salvage therapy is ineffective. Recent studies have shown that some microRNAs (miRNAs) are associated with prognosis, but have not yet explored the role of miRNAs in cellular response to cytarabine. We identified 20 miRNAs that associate with the in vitro cytarabine chemo-sensitivity or apoptotic response of eight AML cell lines. Out of the 20 miRNAs, data on 18 miRNAs was available in AML patients from The Cancer Genome Atlas database. Our stepwise-integrated analyses (step 1-miRNA-target mRNA that were significantly correlated in AML patients; step 2-mRNAs from step 1 with significant association with overall survival (OS)) identified 23 unique miRNA-mRNA pairs predictive of OS in AML patients. As expected HOX genes (HOXA9, HOXB7, and HOXA10) were identified to be regulated by miRs as well as predictive of worse OS. Additionally, miR107-Myb, miR-378-granzyme B involved in granzyme signaling and miR10a-MAP4K4 were identified to be predictive of outcome through integrated analysis. Although additional functional validations to establish clinical/pharmacologic importance of miRNA-mRNA pairs are needed, our results from RNA electrophoretic mobility shift assay confirmed binding of miR-10a, miR-378, and miR-107 with their target genes GALNT1, GZMB, and MYB, respectively. Integration of pathogenic and pharmacologically significant miRNAs and miRNA-mRNA relationships identified in our study opens up opportunities for development of targeted/miRNA-directed therapies.

Original languageEnglish (US)
Article number324
JournalFrontiers in Pharmacology
Volume6
Issue numberJAN
DOIs
StatePublished - Jan 28 2016
Externally publishedYes

Fingerprint

MicroRNAs
Acute Myeloid Leukemia
Messenger RNA
Cytarabine
Granzymes
Survival
In Vitro Techniques
Salvage Therapy
Atlases
Electrophoretic Mobility Shift Assay
Myeloid Cells
Therapeutics
Genes
Genome
Databases
RNA
Recurrence
Cell Line

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)

Cite this

MicroRNA-mRNA pairs associated with outcome in AML : From in vitro cell-based studies to AML patients. / Bhise, Neha S.; Chauhan, Lata; Shin, Miyoung; Cao, Xueyuan; Pounds, Stanley; Lamba, Vishal; Lamba, Jatinder K.

In: Frontiers in Pharmacology, Vol. 6, No. JAN, 324, 28.01.2016.

Research output: Contribution to journalArticle

Bhise, Neha S. ; Chauhan, Lata ; Shin, Miyoung ; Cao, Xueyuan ; Pounds, Stanley ; Lamba, Vishal ; Lamba, Jatinder K. / MicroRNA-mRNA pairs associated with outcome in AML : From in vitro cell-based studies to AML patients. In: Frontiers in Pharmacology. 2016 ; Vol. 6, No. JAN.
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AU - Cao, Xueyuan

AU - Pounds, Stanley

AU - Lamba, Vishal

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AB - Cytarabine is the primary chemotherapeutic agent used for treatment of acute myeloid leukemia (AML). Disease relapse after initial remission remains one of the most pressing therapeutic challenges in the treatment of AML. Relapsed disease is often resistant to cytarabine and subsequent salvage therapy is ineffective. Recent studies have shown that some microRNAs (miRNAs) are associated with prognosis, but have not yet explored the role of miRNAs in cellular response to cytarabine. We identified 20 miRNAs that associate with the in vitro cytarabine chemo-sensitivity or apoptotic response of eight AML cell lines. Out of the 20 miRNAs, data on 18 miRNAs was available in AML patients from The Cancer Genome Atlas database. Our stepwise-integrated analyses (step 1-miRNA-target mRNA that were significantly correlated in AML patients; step 2-mRNAs from step 1 with significant association with overall survival (OS)) identified 23 unique miRNA-mRNA pairs predictive of OS in AML patients. As expected HOX genes (HOXA9, HOXB7, and HOXA10) were identified to be regulated by miRs as well as predictive of worse OS. Additionally, miR107-Myb, miR-378-granzyme B involved in granzyme signaling and miR10a-MAP4K4 were identified to be predictive of outcome through integrated analysis. Although additional functional validations to establish clinical/pharmacologic importance of miRNA-mRNA pairs are needed, our results from RNA electrophoretic mobility shift assay confirmed binding of miR-10a, miR-378, and miR-107 with their target genes GALNT1, GZMB, and MYB, respectively. Integration of pathogenic and pharmacologically significant miRNAs and miRNA-mRNA relationships identified in our study opens up opportunities for development of targeted/miRNA-directed therapies.

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