Open Access
ARTICLE
miRNA–mRNA Profiling Reveals Prognostic Impact of SMC1A Expression in Acute Myeloid Leukemia
Nikhil Gadewal*1, Rohit Kumar†1, Swapnil Aher†, Anagha Gardane†, Tarang Gaur†, Ashok K. Varma*‡§, Navin Khattry¶, Syed K. Hasan†§¶
* Bioinformatics Centre, Advanced Centre for Treatment, Research and Education in Cancer (ACTREC), Navi Mumbai, India
† Cell and Tumor Biology Group, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
‡ Varma Laboratory, Advanced Centre for Treatment, Research and Education in Cancer, Navi Mumbai, India
§ Homi Bhabha National Institute (HBNI), Anushaktinagar, Mumbai, India
¶ Adult Hemato-lymphoid Disease Management Group, Tata Memorial Hospital, Mumbai, India
Oncology Research 2020, 28(3), 321-330. https://doi.org/10.3727/096504020X15816752427321
Abstract
Acute myeloid leukemia (AML) with
NPM1 mutation is a disease driving genetic alteration with good prognosis. Although it has been suggested that
NPM1 mutation induces chemosensitivity in leukemic cells, the
underlying cause for the better survival of
NPM1 mutated patients is still not clear. Mutant
NPM1 AML has
a unique microRNA and their target gene (mRNA) signature compared to wild-type
NPM1. 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
NPM1 mutated (
n = 21) and
NPM1 wild-type (
n = 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
NPM1 mutated and wild-type
allele. The comparison of in vitro transcriptomics data with in silico miRNA–mRNA expression network data
revealed downregulation of
SMC1A. On establishing miRNA–mRNA interactive pairs, it has been observed
that hsa-mir-215-5p (logFC: 0.957;
p = 0.0189) is involved in the downregulation of
SMC1A (logFC: –0.481;
p = 0.0464) in
NPM1 mutated AML. We demonstrated that transient expression of
NPM1 mutation upregulates miR-215-5p, which results in downregulation of
SMC1A. We have also shown using a rescue experiment
that neutralizing miR-215-5p reverses the effect of
NPM1 mutation on
SMC1A. Using the leukemic blasts
from AML patients, we observed higher expression of miR-215-5p and lower expression of
SMC1A in
NPM1
mutated patients compared to wild-type cases. The overall survival of AML patients was significantly inferior
in
SMC1A high expressers compared to low expressers (20.3% vs. 58.5%,
p = 0.018). The data suggest that
dynamic miR-215-
SMC1A regulation is potentially modulated by
NPM1 mutation, which might serve as an
explanation for the better outcome in
NPM1 mutated AML.
Keywords
Cite This Article
Gadewal, N., Kumar, R., Aher, S., Gardane, A., Gaur, T. et al. (2020). miRNA–mRNA Profiling Reveals Prognostic Impact of
SMC1A Expression in Acute Myeloid Leukemia.
Oncology Research, 28(3), 321–330.