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 Blood, 19 February 2009, Vol. 113, No. 8, pp. 1689-1698.
Prepublished online as a Blood First Edition Paper on November 10, 2008; DOI 10.1182/blood-2008-03-147967.

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IMMUNOBIOLOGY

Notch signaling mediates G1/S cell-cycle progression in T cells via cyclin D3 and its dependent kinases

Ila Joshi1,2, Lisa M. Minter2, Janice Telfer1,2, Renée M. Demarest3, Anthony J. Capobianco3, Jon C. Aster4, Piotr Sicinski5, Abdul Fauq6, Todd E. Golde6, and Barbara A. Osborne1,2

1 Program in Molecular and Cell Biology and 2 Department of Veterinary & Animal Sciences, University of Massachusetts, Amherst; 3 Molecular and Cellular Oncogenesis, The Wistar Institute, Philadelphia, PA; 4 Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA; 5 Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Pathology, Harvard Medical School, Boston, MA; and 6 Department of Neuroscience, Mayo Clinic Jacksonville, FL

Notch signaling plays a role in normal lymphocyte development and function. Activating Notch1-mutations, leading to aberrant downstream signaling, have been identified in human T-cell acute lymphoblastic leukemia (T-ALL). While this highlights the contribution of Notch signaling to T-ALL pathogenesis, the mechanisms by which Notch regulates proliferation and survival in normal and leukemic T cells are not fully understood. Our findings identify a role for Notch signaling in G1-S progression of cell cycle in T cells. Here we show that expression of the G1 proteins, cyclin D3, CDK4, and CDK6, is Notch-dependent both in vitro and in vivo, and we outline a possible mechanism for the regulated expression of cyclin D3 in activated T cells via CSL (CBF-1, mammals; suppressor of hairless, Drosophila melanogaster; Lag-1, Caenorhabditis elegans), as well as a noncanonical Notch signaling pathway. While cyclin D3 expression contributes to cell-cycle progression in Notch-dependent human T-ALL cell lines, ectopic expression of CDK4 or CDK6 together with cyclin D3 shows partial rescue from {gamma}-secretase inhibitor (GSI)-induced G1 arrest in these cell lines. Importantly, cyclin D3 and CDK4 are highly overexpressed in Notch-dependent T-cell lymphomas, justifying the combined use of cell-cycle inhibitors and GSI in treating human T-cell malignancies.


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