Therapeutic Targeting of the Cyclin D3:CDK4/6 Complex in T Cell Leukemia

Department of Pathology and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
Cancer cell (Impact Factor: 23.52). 10/2012; 22(4):452-65. DOI: 10.1016/j.ccr.2012.09.016
Source: PubMed


D-type cyclins form complexes with cyclin-dependent kinases (CDK4/6) and promote cell cycle progression. Although cyclin D functions appear largely tissue specific, we demonstrate that cyclin D3 has unique functions in lymphocyte development and cannot be replaced by cyclin D2, which is also expressed during blood differentiation. We show that only combined deletion of p27(Kip1) and retinoblastoma tumor suppressor (Rb) is sufficient to rescue the development of Ccnd3(-/-) thymocytes. Furthermore, we show that a small molecule targeting the kinase function of cyclin D3:CDK4/6 inhibits both cell cycle entry in human T cell acute lymphoblastic leukemia (T-ALL) and disease progression in animal models of T-ALL. These studies identify unique functions for cyclin D3:CDK4/6 complexes and suggest potential therapeutic protocols for this devastating blood tumor.

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    • "This work also demonstrated that cyclin-D3 has a unique role in the expansion of normally developing T-cell progenitors and in the induction of T-ALL. Forced in vivo expression of cyclin-D2 did not compensate for the lack of cyclin-D3, suggesting intrinsic differences in the function of these two proteins in T-cell development (75). Collectively, these studies demonstrate a new avenue for targeted therapies directed against cell-cycle regulators in T-ALL. "
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