Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1
Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematop...
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| Veröffentlicht in: | Leukemia 2016-10, Vol.30 (10), p.2002 |
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| creator | Gekas, C D%apos Altri, T Aligué, R González, J Espinosa, L Bigas, A |
| description | Notch activation is instrumental in the development of most T-cell acute lymphoblastic leukemia (T-ALL) cases, yet Notch mutations alone are not sufficient to recapitulate the full human disease in animal models. We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of [beta]-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of [beta]-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of [beta]-Catenin in these T-ALL cells and demonstrate that the MYC 3' enhancer required [beta]-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1. Leukemia (2016) 30, 2002-2010; doi: 10.1038/leu.2016.106; published online 17 May 2016 |
| doi_str_mv | 10.1038/leu.2016.106 |
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We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of [beta]-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of [beta]-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of [beta]-Catenin in these T-ALL cells and demonstrate that the MYC 3' enhancer required [beta]-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1. 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We here found that Notch1 activation at the fetal liver (FL) stage expanded the hematopoietic progenitor population and conferred it transplantable leukemic-initiating capacity. However, leukemogenesis and leukemic-initiating cell capacity induced by Notch1 was critically dependent on the levels of [beta]-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of [beta]-Catenin compromised survival and proliferation of human T-ALL cell lines carrying activated Notch1. By transcriptome analyses, we identified the MYC pathway as a crucial element downstream of [beta]-Catenin in these T-ALL cells and demonstrate that the MYC 3' enhancer required [beta]-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1. Leukemia (2016) 30, 2002-2010; doi: 10.1038/leu.2016.106; published online 17 May 2016</abstract><cop>London</cop><pub>Nature Publishing Group</pub><doi>10.1038/leu.2016.106</doi></addata></record> |
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| subjects | Acute lymphocytic leukemia Analysis Animal experimentation Antibodies Bone marrow Cancer research Care and treatment Cell cycle Cyclin-dependent kinases Cytokines Kinases Leukemia Medical research Mutation Stem cells T cells Transcription (Genetics) |
| title | Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1 |
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