A Genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets
- Sophia Adamia
- Benjamin Haibe-Kains
- Patrick M. Pilarski
- Michal Bar-Natan
- Samuel Pevzner
- Herve Avet-Loiseau
- Laurence Lode
- Sigitas Verselis
- Edward A. Fox
- John Burke
- Ilene Galinsky
- Ibiayi Dagogo-Jack
- Martha Wadleigh
- David P. Steensma
- Gabriela Motyckova
- Daniel J. Deangelo
- John Quackenbush
- Richard Stone
- James D. Griffin
Purpose: Despite new treatments, acute myeloid leukemia (AML) remains an incurable disease. More effective drug design requires an expanded view of the molecular complexity that underlies AML. Alternative splicing of RNA is used by normal cells to generate protein diversity. Growing evidence indicates that aberrant splicing of genes plays a key role in cancer. We investigated genome-wide splicing abnormalities in AML and based on these abnormalities, we aimed to identify novel potential biomarkers and therapeutic targets. Experimental Design: We used genome-wide alternative splicing screening to investigate alternative splicing abnormalities in two independent AML patient cohorts [Dana-Farber Cancer Institute (DFCI) (Boston, MA) and University Hospital de Nantes (UHN) (Nantes, France)] and normal donors. Selected splicing events were confirmed through cloning and sequencing analysis, and than validated in 193 patients with AML. Results: Our results show that approximately 29% of expressed genes genome-wide were differentially and recurrently spliced in patients with AML compared with normal donors bone marrow CD34+ cells. Results were reproducible in two independent AML cohorts. In both cohorts, annotation analyses indicated similar proportions of differentially spliced genes encoding several oncogenes, tumor suppressor proteins, splicing factors, and heterogeneous-nuclear-ribonucleoproteins, proteins involved in apoptosis, cell proliferation, and spliceosome assembly. Our findings are consistent with reports for other malignances and indicate that AML-specific aberrations in splicing mechanisms are a hallmark of AML pathogenesis. Conclusions: Overall, our results suggest that aberrant splicing is a common characteristic for AML. Our findings also suggest that splice variant transcripts that are the result of splicing aberrations create novel disease markers and provide potential targets for small molecules or antibody therapeutics for this disease.
Citation
S. Adamia, B. Haibe-Kains, P. Pilarski, M. Bar-Natan, S. Pevzner, H. Avet-Loiseau, L. Lode, S. Verselis, E. Fox, J. Burke, I. Galinsky, I. Dagogo-Jack, M. Wadleigh, D. Steensma, G. Motyckova, D. Deangelo, J. Quackenbush, R. Stone, J. Griffin. "A Genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets". Clinical Cancer Research (CCR), 20(5), pp 1135-1145, March 2014.| Keywords: | |
| Category: | In Journal |
| Web Links: | doi |
BibTeX
@article{Adamia+al:CCR14,
author = {Sophia Adamia and Benjamin Haibe-Kains and Patrick M. Pilarski and
Michal Bar-Natan and Samuel Pevzner and Herve Avet-Loiseau and Laurence
Lode and Sigitas Verselis and Edward A. Fox and John Burke and Ilene
Galinsky and Ibiayi Dagogo-Jack and Martha Wadleigh and David P. Steensma
and Gabriela Motyckova and Daniel J. Deangelo and John Quackenbush and
Richard Stone and James D. Griffin},
title = {A Genome-wide aberrant RNA splicing in patients with acute myeloid
leukemia identifies novel potential disease markers and therapeutic
targets},
Volume = "20",
Number = "5",
Pages = {1135-1145},
journal = {Clinical Cancer Research (CCR)},
year = 2014,
}Last Updated: November 10, 2020Submitted by Sabina P
