A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets
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Abstract
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.
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Alternative splicing abnormalities play a pivotal role in leukemia pathogenesis.
“Current evidence suggests a pivotal role of alternative splicing abnormalities in leukemia pathogenesis (12,13).”
From Discovery of a Novel CIP2A Variant (NOCIVA) with Clinical Relevance in Predicting TKI Resistance in Myeloid Leukemias (2021) · cites this paper as [13]
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- Authors
- Adamia, S., Haibe-Kains, B., Pilarski, P. M., Bar-Natan, M., Pevzner, S., Avet-Loiseau, H., Lode, L., Verselis, S., Fox, E. A., Burke, J., Galinsky, I., Dagogo-Jack, I., Wadleigh, M., Steensma, D. P., Motyckova, G., Deangelo, D. J., Quackenbush, J., Stone, R., & Griffin, J. D.
- Affiliations
- Boston University (US)
- Authors' Affiliations: 1Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; 2Bioinformatics and Computational Genomics Laboratory, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada; 3Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada; 4Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; 5Dana-Farber Cancer Institute, Center for Cancer Systems Biology and Department of Genetics, Harvard Medical School, Boston University School of Medicine and Biomedical Engineering Department, Boston University, Boston, Massachusetts; 6Unité de Génomique du Myélome, Laboratoire UGM, University Hospital, CHU Rangueil, Toulouse, France; 7Hematology Laboratory, University Hospital; and INSERM U892, Nantes, France; 8Molecular Diagnostics Laboratory, Dana Farber Cancer Institute, Boston, Massachusetts; 9Biotique Systems Inc., www.biotiquesystems.com; 10Adult Leukemia Program, Dana
- ORCID
- Venue
- Clinical Cancer Research
- Published
- 2014-03-01
- Volume
- 20
- Issue
- 5
- Pages
- 1135-1145
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC4458245
- OpenAlex
- W2140352493
- Cited by
- 106
- References
- 44
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 8 · 2023: 13 · 2022: 6 · 2021: 10 · 2020: 13 · 2019: 6 · 2018: 7 · 2017: 8 · 2016: 7 · 2015: 8 · 2014: 13
- FWCI
- 4.18
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01lm010129-02)
- National Cancer Institute (P01CA066996)
- U.S. National Library of Medicine (R01-LM010129, R01 LM010129-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- acute myeloid leukemia, alternative splicing, aberrant splicing, therapeutic target, splice variants, splicing factors, spliceosome, oncogenes, tumor suppressor, CD34+ bone marrow cells, leukemogenesis
- MeSH terms
- Gene Frequency, Humans, RNA Splicing, Biomarkers, Tumor, Reproducibility of Results, Signal Transduction, Leukemia, Myeloid, Acute, Alternative Splicing, CD13 Antigens, Gene Expression Profiling, Genome-Wide Association Study, Molecular Sequence Annotation, Molecular Targeted Therapy
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