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Acute lymphoblastic leukemia

CDK6-mediated repression of CD25 is required for induction and maintenance of Notch1-induced T-cell acute lymphoblastic leukemia

Leukemia volume 30, pages 1033–1043 (2016)Cite this article

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Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subset of acute leukemia, characterized by frequent activation of Notch1 or AKT signaling, where new therapeutic approaches are needed. We showed previously that cyclin-dependent kinase 6 (CDK6) is required for thymic lymphoblastic lymphoma induced by activated AKT. Here, we show CDK6 is required for initiation and maintenance of Notch-induced T-ALL. In a mouse retroviral model, hematopoietic stem/progenitor cells lacking CDK6 protein or expressing kinase-inactive (K43M) CDK6 are resistant to induction of T-ALL by activated Notch, whereas those expressing INK4-insensitive (R31C) CDK6 are permissive. Pharmacologic inhibition of CDK6 kinase induces CD25 and RUNX1 expression, cell cycle arrest and apoptosis in mouse and human T-ALL. Ablation of Cd25 in a K43M background restores Notch-induced T leukemogenesis, with disease that is resistant to CDK6 inhibitors in vivo. These data support a model whereby CDK6-mediated suppression of CD25 is required for initiation of T-ALL by activated Notch1, and CD25 induction mediates the therapeutic response to CDK6 inhibition in established T-ALL. These results both validate CDK6 as a molecular target for therapy of this subset of T-ALL and suggest that CD25 expression could serve as a biomarker for responsiveness of T-ALL to CDK4/6 inhibitor therapy.

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Acknowledgements

We thank Dr Jon Aster (Brigham and Women's Hospital, Boston, MA, USA) for MigR1-ICN retrovirus and human T-ALL cell lines, and Dr Harald von Boehmer (Dana-Farber Cancer Institute, Boston, MA, USA) for ICN-DsRed and DsRed-V retroviruses. We thank Dr Michelle Kelliher (UMass Medical School) for human T-ALL cell lines with wild-type Notch1 receptor. We thank Novartis Institutes for Biomedical Research (Cambridge, MA, USA) for LEE011. This work was supported by a V Foundation Translational Research Grant, Tufts Medical Center Research Fund, a Tufts CTSI-Catalyst Award (UL1 TR001064) and Tufts University Seed Grants to MGH; R01 CA090576 to RAV; R01 CA127392 to PWH; and R01 CA105241 and R01 NS065237 to GFH

Author contributions

NJ designed and performed the experiments, analyzed the data and interpreted the results; JS, JKH, WL, WZ, GL, NT, AP, NB, AD and CL assisted in genotyping and performed the experiments; GFH and PWH provided the guidance and reagents; RVE provided the guidance for the group and assisted in the manuscript preparation; and MGH designed and performed the experiments, interpreted the results, provided the guidance for the group and wrote the manuscript.

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Author notes

  1. N Jena & R A Van Etten

    Present address: 2Current address: Chao Family Comprehensive Cancer Center, University of California Irvine, Irvine, CA, USA.,

  2. P W Hinds

    Present address: 3Current address: Tufts University School of Medicine, Boston, MA, USA.,

Authors and Affiliations

  1. Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA

    N Jena, J Sheng, J K Hu, W Li, W Zhou, G Lee, N Tsichlis, A Pathak, N Brown, A Deshpande, C Luo, G F Hu, P W Hinds, R A Van Etten & M G Hu

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  1. N Jena
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Correspondence to M G Hu.

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Jena, N., Sheng, J., Hu, J. et al. CDK6-mediated repression of CD25 is required for induction and maintenance of Notch1-induced T-cell acute lymphoblastic leukemia. Leukemia 30, 1033–1043 (2016). https://doi.org/10.1038/leu.2015.353

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