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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    • "Several such efforts are currently under way. Briefly, investigators have demonstrated in vivo T-ALL remission by targeting (1) the NOTCH1-induced IKK kinase complex, which plays a pivotal role in controlling the NF-kB pathway, which in turn is strongly related to NOTCH in leukemia (Figure 4; Dan et al., 2008; Espinosa et al., 2010; Vilimas et al., 2007); (2) the CyclinD:CDK4/6 kinase complex, which is hyperactivated in this type of acute leukemia (Sawai et al., 2012); and (3) the bromodomain-containing protein BRD4 (King et al., 2013). BRD proteins can be transcriptional coactivators and share common binding patterns with T-ALL oncogenes NOTCH1 and MYC in promoters and enhancers of key genes for the induction and progression of the disease. "
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    • "When dissecting the signaling pathway of the T. cruzi-mediated inhibition of T cell responses, we found that the parasite mucin was able to induce G1 cell cycle arrest associated with upregulation of the cyclin D inhibitor p27(kip1) and downmodulation of cyclin D3 on activated CD4+ T cells [69]. p27 is a phosphatase regulator that participates in the G1 cell cycle arrest checkpoint [82–84]. In contrast, when CD4+ T cells were polyclonally activated in the presence of desialylated T. cruzi mucin the signaling profile was reversed as demonstrated by the upregulation of cyclin D3 and downmodulation of p27(kip1), a profile similar to that described for control TCR-activated T cells. "
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