Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.

TitleTherapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.
Publication TypeJournal Article
Year of Publication2012
AuthorsSawai CM, Freund J, Oh P, Ndiaye-Lobry D, Bretz JC, Strikoudis A, Genesca L, Trimarchi T, Kelliher MA, Clark M, Soulier J, Chen-Kiang S, Aifantis I
JournalCancer Cell
Volume22
Issue4
Pagination452-65
Date Published2012 Oct 16
ISSN1878-3686
KeywordsAnimals, Cyclin D2, Cyclin D3, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Cyclin-Dependent Kinase Inhibitor p27, Humans, Lymphocytes, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Receptor, Notch1, Retinoblastoma Protein
Abstract

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.

DOI10.1016/j.ccr.2012.09.016
Alternate JournalCancer Cell
PubMed ID23079656
PubMed Central IDPMC3493168
Grant ListR01CA133379 / CA / NCI NIH HHS / United States
R01GM088847 / GM / NIGMS NIH HHS / United States
R01CA149655 / CA / NCI NIH HHS / United States
R01CA105129 / CA / NCI NIH HHS / United States
P30 CA016087-30 / CA / NCI NIH HHS / United States
5 P30CA16087-31 / CA / NCI NIH HHS / United States
5P30CA16087-31 / CA / NCI NIH HHS / United States
R21CA141399 / CA / NCI NIH HHS / United States
Related Lab: 
Related Faculty: 
Selina Chen-Kiang, Ph.D.

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