title: NOTCH2 and FLT3 gene mis-splicings are common events in patients with acute myeloid leukemia (AML): new potential targets in AML.
abstract: Our previous studies revealed an increase in alternative splicing of multiple RNAs in cells from patients with acute myeloid leukemia (AML) compared with CD34(+) bone marrow cells from normal donors. Aberrantly spliced genes included a number of oncogenes, tumor suppressor genes, and genes involved in regulation of apoptosis, cell cycle, and cell differentiation. Among the most commonly mis-spliced genes (>70% of AML patients) were 2, NOTCH2 and FLT3, that encode myeloid cell surface proteins. The splice variants of NOTCH2 and FLT3 resulted from complete or partial exon skipping and utilization of cryptic splice sites. Longitudinal analyses suggested that NOTCH2 and FLT3 aberrant splicing correlated with disease status. Correlation analyses between splice variants of these genes and clinical features of patients showed an association between NOTCH2-Va splice variant and overall survival of patients. Our results suggest that NOTCH2 and FLT3 mis-splicing is a common characteristic of AML and has the potential to generate transcripts encoding proteins with altered function. Thus, splice variants of these genes might provide disease markers and targets for novel therapeutics.
authors.affiliation: Medical Oncology, Dana-Farber Cancer Institute, and.
authors.forename: Sophia
authors.initials: S
authors.lastname: Adamia
authors.forename: Michal
authors.initials: M
authors.lastname: Bar-Natan
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Pilarski
authors.forename: Christian
authors.initials: C
authors.lastname: Bach
authors.forename: Samuel
authors.initials: S
authors.lastname: Pevzner
authors.forename: Teresa
authors.initials: T
authors.lastname: Calimeri
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: Ilene
authors.initials: I
authors.lastname: Galinsky
authors.forename: Steven
authors.initials: S
authors.lastname: Mathews
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: Daniel G
authors.initials: DG
authors.lastname: Tenen
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: James D
authors.initials: JD
authors.lastname: Griffin
mesh_terms: D017398:Alternative Splicing; D002460:Cell Line; D016000:Cluster Analysis; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008565:Membrane Proteins / Q000378:metabolism; D011379:Prognosis; D051883:Receptor, Notch2 / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D016896:Treatment Outcome; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics* / Q000378:metabolism
chemical_list: D008565:Membrane Proteins; D051883:Receptor, Notch2; C084881:flt3 ligand protein; D051941:fms-Like Tyrosine Kinase 3