@Article{096504020X15816752427321,
AUTHOR = {Nikhil Gadewal, Rohit Kumar, Swapnil Aher, Anagha Gardane, Tarang Gaur, Ashok K. Varma, Navin Khattry, Syed K. Hasan},
TITLE = {miRNA–mRNA Profiling Reveals Prognostic Impact of <i>SMC1A</i>  Expression in Acute Myeloid Leukemia},
JOURNAL = {Oncology Research},
VOLUME = {28},
YEAR = {2020},
NUMBER = {3},
PAGES = {321--330},
URL = {http://www.techscience.com/or/v28n3/48535},
ISSN = {1555-3906},
ABSTRACT = {Acute myeloid leukemia (AML) with <i>NPM1</i> mutation is a disease driving genetic alteration with good prognosis. Although it has been suggested that <i>NPM1</i> mutation induces chemosensitivity in leukemic cells, the 
underlying cause for the better survival of <i>NPM1</i> mutated patients is still not clear. Mutant <i>NPM1</i> AML has 
a unique microRNA and their target gene (mRNA) signature compared to wild-type <i>NPM1</i>. Dynamic regulation of miRNA–mRNA has been reported to influence the prognostic outcome. In the present study, in silico 
expression data of miRNA and mRNA in AML patients was retrieved from genome data commons, and differentially expressed miRNA and mRNA among <i>NPM1</i> mutated (<i>n</i> = 21) and <i>NPM1</i> wild-type (<i>n</i> = 162) cases 
were identified to establish a dynamic association at the molecular level. In vitro experiments using highthroughput RNA sequencing were performed on human AML cells carrying <i>NPM1</i> mutated and wild-type 
allele. The comparison of in vitro transcriptomics data with in silico miRNA–mRNA expression network data 
revealed downregulation of <i>SMC1A</i>. On establishing miRNA–mRNA interactive pairs, it has been observed 
that hsa-mir-215-5p (logFC: 0.957; <i>p</i> = 0.0189) is involved in the downregulation of <i>SMC1A</i> (logFC: –0.481; 
<i>p</i> = 0.0464) in <i>NPM1</i> mutated AML. We demonstrated that transient expression of <i>NPM1</i> mutation upregulates miR-215-5p, which results in downregulation of <i>SMC1A</i>. We have also shown using a rescue experiment 
that neutralizing miR-215-5p reverses the effect of <i>NPM1</i> mutation on <i>SMC1A</i>. Using the leukemic blasts 
from AML patients, we observed higher expression of miR-215-5p and lower expression of <i>SMC1A</i> in <i>NPM1</i>
mutated patients compared to wild-type cases. The overall survival of AML patients was significantly inferior 
in <i>SMC1A</i> high expressers compared to low expressers (20.3% vs. 58.5%, <i>p</i> = 0.018). The data suggest that 
dynamic miR-215-<i>SMC1A</i> regulation is potentially modulated by <i>NPM1</i> mutation, which might serve as an 
explanation for the better outcome in <i>NPM1</i> mutated AML.},
DOI = {10.3727/096504020X15816752427321}
}