title: CDK6-mediated repression of CD25 is required for induction and maintenance of Notch1-induced T-cell acute lymphoblastic leukemia.
abstract: T-cell acute lymphoblastic leukemia (T-ALL) is a high-risk subset of acute leukemia, characterized by frequent activation of Notch1 or AKT signaling, where new therapeutic approaches are needed. We showed previously that cyclin-dependent kinase 6 (CDK6) is required for thymic lymphoblastic lymphoma induced by activated AKT. Here, we show CDK6 is required for initiation and maintenance of Notch-induced T-ALL. In a mouse retroviral model, hematopoietic stem/progenitor cells lacking CDK6 protein or expressing kinase-inactive (K43M) CDK6 are resistant to induction of T-ALL by activated Notch, whereas those expressing INK4-insensitive (R31C) CDK6 are permissive. Pharmacologic inhibition of CDK6 kinase induces CD25 and RUNX1 expression, cell cycle arrest and apoptosis in mouse and human T-ALL. Ablation of Cd25 in a K43M background restores Notch-induced T leukemogenesis, with disease that is resistant to CDK6 inhibitors in vivo. These data support a model whereby CDK6-mediated suppression of CD25 is required for initiation of T-ALL by activated Notch1, and CD25 induction mediates the therapeutic response to CDK6 inhibition in established T-ALL. These results both validate CDK6 as a molecular target for therapy of this subset of T-ALL and suggest that CD25 expression could serve as a biomarker for responsiveness of T-ALL to CDK4/6 inhibitor therapy.
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Jena
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: J
authors.initials: J
authors.lastname: Sheng
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Hu
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Li
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: W
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Tsichlis
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Pathak
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: N
authors.initials: N
authors.lastname: Brown
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Deshpande
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: C
authors.identifier: 0000-0001-7669-9506
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: G F
authors.initials: GF
authors.lastname: Hu
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: P W
authors.initials: PW
authors.lastname: Hinds
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Van Etten
authors.affiliation: Department of Medicine, Molecular Oncology Research Institute, Tufts Medical Center, Boston, MA, USA.
authors.forename: M G
authors.initials: MG
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D063646:Carcinogenesis / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology*; D051881:Receptor, Notch1 / Q000378:metabolism / Q000502:physiology*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6