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Acute lymphoblastic leukemia

β-Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1

Leukemia volume 30, pages 2002–2010 (2016)Cite this article

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Abstract

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 β-Catenin in both FL and adult bone marrow contexts. In addition, inhibition of β-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 β-Catenin in these T-ALL cells and demonstrate that the MYC 3′ enhancer required β-Catenin and Notch1 recruitment to induce transcription. Finally, PKF115-584 treatment prevented and partially reverted leukemogenesis induced by active Notch1.

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Acknowledgements

We thank Carla Bello for RNA-Seq data mapping and analysis; Iannis Aifantis and Apostolos Klinakis for EF1a-LSL-N1IC mice and retroviral constructs; Steve Blacklow and Sarah Bray for helpful discussions; Jon Aster for anti-N1 antibody; and Warren Pear for myc enhancer constructs and helpful discussions. This research was funded by the Worldwide Cancer Research (formerly AICR, 13-0064), Fundación AECC (Cancer infantil), Ministerio de Economía y Competitividad (SAF2013-40922-R), Red Temática de Investigación Cooperativa en Cáncer (RD12/0036/0054) and Agència de Gestió d’Ajuds Universitaris i de Recerca (AGAUR) (2014SGR-124) to AB.

Author contributions

CG, LE and AB designed experiments, analyzed data and wrote the manuscript; CG, TD, LE, RA and JG conducted experiments.

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Author notes

  1. L Espinosa and A Bigas: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Cancer Research, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Barcelona, Spain

    C Gekas, T D’Altri, J González, L Espinosa & A Bigas

  2. Department of Cell Biology, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain

    R Aligué

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  1. C Gekas
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Correspondence to A Bigas.

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Gekas, C., D’Altri, T., Aligué, R. et al. β-Catenin is required for T-cell leukemia initiation and MYC transcription downstream of Notch1. Leukemia 30, 2002–2010 (2016). https://doi.org/10.1038/leu.2016.106

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