title: A genome-wide aberrant RNA splicing in patients with acute myeloid leukemia identifies novel potential disease markers and therapeutic targets.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Bioinformatics and Computational Genomics Laboratory, Institut de Recherches Cliniques de Montréal, Montreal, Quebec, Canada; Department of Computing Science, University of Alberta, Edmonton, Alberta, Canada; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Dana-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; Unité de Génomique du Myélome, Laboratoire UGM, University Hospital, CHU Rangueil, Toulouse, France; Hematology Laboratory, University Hospital; and INSERM U892, Nantes, France; Molecular Diagnostics Laboratory, Dana Farber Cancer Institute, Boston, Massachusetts; Biotique Systems Inc., www.biotiquesystems.com; Adult Leukemia Program, Dana Farber Cancer Institute, Boston, Massachusetts; Brigham and Women's Hospital, Boston, Massachusetts; Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Pilarski
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.forename: Samuel
authors.initials: S
authors.lastname: Pevzner
authors.forename: Herve
authors.initials: H
authors.lastname: Avet-Loiseau
authors.forename: Laurence
authors.initials: L
authors.lastname: Lode
authors.forename: Sigitas
authors.initials: S
authors.lastname: Verselis
authors.forename: Edward A
authors.initials: EA
authors.lastname: Fox
authors.forename: John
authors.initials: J
authors.lastname: Burke
authors.forename: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Ibiayi
authors.initials: I
authors.lastname: Dagogo-Jack
authors.forename: Martha
authors.initials: M
authors.lastname: Wadleigh
authors.forename: David P
authors.initials: DP
authors.lastname: Steensma
authors.forename: Gabriela
authors.initials: G
authors.lastname: Motyckova
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Deangelo
authors.forename: John
authors.initials: J
authors.lastname: Quackenbush
authors.forename: Richard
authors.initials: R
authors.lastname: Stone
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D017398:Alternative Splicing; D014408:Biomarkers, Tumor; D018826:CD13 Antigens / Q000235:genetics; D020869:Gene Expression Profiling; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D058977:Molecular Sequence Annotation; D058990:Molecular Targeted Therapy; D012326:RNA Splicing; D015203:Reproducibility of Results; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; D018826:CD13 Antigens