CDK6-mediated repression of CD25 is required for induction and maintenance of Notch1-induced T-cell acute lymphoblastic leukemia

• Published in: Leukemia 2016-05, Vol.30 (5), p.1033-1043
• Main Authors: Jena, N, Sheng, J, Hu, J K, Li, W, Zhou, W, Lee, G, Tsichlis, N, Pathak, A, Brown, N, Deshpande, A, Luo, C, Hu, G F, Hinds, P W, Van Etten, R A, Hu, M G
• Format: Article
• Language: English
• Subjects: 38; 38/77; 42; 42/41; 45; 45/100; 45/22; 631/67/1059/602; 631/67/1990/283/1895; 631/67/1990/283/2125; 631/67/395; 631/80/86; 692/53; Ablation; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; AKT protein; Animals; Apoptosis; Apoptosis - drug effects; Biomarkers; Cancer Research; Cancer therapies; Carcinogenesis - metabolism; Care and treatment; CD25 antigen; Cell cycle; Cell Cycle Checkpoints - drug effects; Cells (biology); Cellular signal transduction; Core Binding Factor Alpha 2 Subunit - metabolism; Critical Care Medicine; Cyclin-Dependent Kinase 4 - antagonists & inhibitors; Cyclin-dependent kinase 6; Cyclin-Dependent Kinase 6 - antagonists & inhibitors; Cyclin-Dependent Kinase 6 - physiology; Cyclin-dependent kinases; Development and progression; Gene expression; Genetic aspects; Health aspects; Hematology; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Humans; INK4 protein; Intensive; Interleukin-2 Receptor alpha Subunit - metabolism; Interleukin-2 Receptor alpha Subunit - physiology; Internal Medicine; Kinases; Leukemia; Leukemogenesis; Lymphatic leukemia; Lymphocytes T; Lymphoma; Maintenance; Medicine; Medicine & Public Health; Mice; Mutation; Notch1 protein; Oncology; original-article; Phase transitions; Phosphotransferases; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - etiology; Progenitor cells; Properties; Receptor, Notch1 - metabolism; Receptor, Notch1 - physiology; Runx1 protein; Thymus
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2015.353

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.