Therapeutic targeting of the cyclin D3:CDK4/6 complex in T cell leukemia.
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.
Department of Pathology and Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.
Catherine M
CM
Sawai
Jacquelyn
J
Freund
Philmo
P
Oh
Delphine
D
Ndiaye-Lobry
Jamieson C
JC
Bretz
Alexandros
A
Strikoudis
Lali
L
Genesca
Thomas
T
Trimarchi
Michelle A
MA
Kelliher
Marcus
M
Clark
Jean
J
Soulier
Selina
S
Chen-Kiang
Iannis
I
Aifantis
D000818:Animals; D056742:Cyclin D2 / Q000502:physiology; D056743:Cyclin D3 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors* / Q000502:physiology; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors* / Q000502:physiology; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000502:physiology; D006801:Humans; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000209:etiology; D051881:Receptor, Notch1 / Q000502:physiology; D016160:Retinoblastoma Protein / Q000502:physiology
D056742:Cyclin D2; D056743:Cyclin D3; D051881:Receptor, Notch1; D016160:Retinoblastoma Protein; D050760:Cyclin-Dependent Kinase Inhibitor p27; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6