title: Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia.
abstract: Activating NOTCH1 mutations occur in ~60% of human T-cell acute lymphoblastic leukemias (T-ALLs), and mutations disrupting the transcription factor IKZF1 (IKAROS) occur in ~5% of cases. To investigate the regulatory interplay between these driver genes, we have used a novel transgenic RNA interference mouse model to produce primary T-ALLs driven by reversible Ikaros knockdown. Restoring endogenous Ikaros expression in established T-ALL in vivo acutely represses Notch1 and its oncogenic target genes including Myc, and in multiple primary leukemias causes disease regression. In contrast, leukemias expressing high levels of endogenous or engineered forms of activated intracellular Notch1 (ICN1) resembling those found in human T-ALL rapidly relapse following Ikaros restoration, indicating that ICN1 functionally antagonizes Ikaros in established disease. Furthermore, we find that IKAROS mRNA expression is significantly reduced in a cohort of primary human T-ALL patient samples with activating NOTCH1/FBXW7 mutations, but is upregulated upon acute inhibition of aberrant NOTCH signaling across a panel of human T-ALL cell lines. These results demonstrate for the first time that aberrant NOTCH activity compromises IKAROS function in mouse and human T-ALL, and provide a potential explanation for the relative infrequency of IKAROS gene mutations in human T-ALL.
authors: 1] Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: M T
authors: MT
authors: Witkowski
authors: 1] Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia [3] Department of Pathology, NYU School of Medicine, New York, NY, USA.
authors: L
authors: L
authors: Cimmino
authors: Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors: Y
authors: Y
authors: Hu
authors: Department of Pathology, NYU School of Medicine, New York, NY, USA.
authors: T
authors: T
authors: Trimarchi
authors: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
authors: H
authors: H
authors: Tagoh
authors: 1] Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: M D
authors: MD
authors: McKenzie
authors: 1] Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: S A
authors: SA
authors: Best
authors: 1] Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: L
authors: L
authors: Tuohey
authors: 1] Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: T A
authors: TA
authors: Willson
authors: 1] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia [2] Molecular Immunology Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.
authors: S L
authors: SL
authors: Nutt
authors: Research Institute of Molecular Pathology, Vienna Biocenter, Vienna, Austria.
authors: M
authors: M
authors: Busslinger
authors: Department of Pathology, NYU School of Medicine, New York, NY, USA.
authors: I
authors: I
authors: Aifantis
authors: 1] Bioinformatics Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Mathematics and Statistics, University of Melbourne, Parkville, VIC, Australia.
authors: G K
authors: GK
authors: Smyth
authors: 1] Molecular Medicine Division, Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia [2] Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia.
authors: R A
authors: RA
authors: Dickins
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D047369:Chromatin Immunoprecipitation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005434:Flow Cytometry; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D051740:Ikaros Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D051880:Receptors, Notch; D051740:Ikaros Transcription Factor; D044767:Ubiquitin-Protein Ligases
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