Activated Notch counteracts Ikaros tumor suppression in mouse and human T-cell acute lymphoblastic leukemia
| Autor: | Tracy A. Willson, Meinrad Busslinger, Yifang Hu, Thomas Trimarchi, Sarah A. Best, Matthew T. Witkowski, Luisa Cimmino, Stewart L Nutt, Ioannis Aifantis, Laura Tuohey, Hiromi Tagoh, Gordon K. Smyth, Ross A. Dickins, Mark D. McKenzie |
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| Rok vydání: | 2015 |
| Předmět: |
Chromatin Immunoprecipitation
Cancer Research F-Box-WD Repeat-Containing Protein 7 Ubiquitin-Protein Ligases Blotting Western Notch signaling pathway Cell Cycle Proteins Mice Transgenic Biology Gene mutation Precursor T-Cell Lymphoblastic Leukemia-Lymphoma medicine.disease_cause Article Ikaros Transcription Factor Mice RNA interference Biomarkers Tumor medicine Animals Humans Transcription factor Gene knockdown Mutation Receptors Notch F-Box Proteins High-Throughput Nucleotide Sequencing Hematology Flow Cytometry Haematopoiesis Oncology Immunology Cancer research Signal Transduction |
| Zdroj: | Leukemia. 29:1301-1311 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2015.27 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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