title: Casein kinase 2 controls the survival of normal thymic and leukemic γδ T cells via promotion of AKT signaling.
abstract: The thymus is the major site for normal and leukemic T-cell development. The dissection of the molecular determinants of T-cell survival and differentiation is paramount for the manipulation of healthy or transformed T cells in cancer (immuno)therapy. Casein kinase 2 (CK2) is a serine/threonine protein kinase whose anti-apoptotic functions have been described in various hematological and solid tumors. Here we disclose an unanticipated role of CK2 in healthy human thymocytes that is selective to the γδ T-cell lineage. γδ thymocytes display higher (and T-cell receptor inducible) CK2 activity than their αβ counterparts, and are strikingly sensitive to death upon CK2 inhibition. Mechanistically, we show that CK2 regulates the pro-survival AKT signaling pathway in γδ thymocytes and, importantly, also in γδ T-cell acute lymphoblastic leukemia (T-ALL) cells. When compared with healthy thymocytes or leukemic αβ T cells, γδ T-ALL cells show upregulated CK2 activity, potentiated by CD27 costimulation, and enhanced apoptosis upon CK2 blockade using the chemical inhibitor CX-4945. Critically, this results in inhibition of tumor growth in a xenograft model of human γδ T-ALL. These data identify CK2 as a novel survival determinant of both healthy and leukemic γδ T cells, and may thus greatly impact their therapeutic manipulation.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: S T
authors.initials: ST
authors.lastname: Ribeiro
authors.affiliation: Institut Necker Enfants Malades, Hôpital Necker-Enfants Malades, APHP et Université Paris, Paris, France.
authors.forename: M
authors.initials: M
authors.lastname: Tesio
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: J C
authors.initials: JC
authors.lastname: Ribot
authors.affiliation: Institut Necker Enfants Malades, Hôpital Necker-Enfants Malades, APHP et Université Paris, Paris, France.
authors.forename: E
authors.initials: E
authors.lastname: Macintyre
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: J T
authors.initials: JT
authors.lastname: Barata
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
authors.forename: B
authors.initials: B
authors.lastname: Silva-Santos
mesh_terms: D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000502:physiology*; D002470:Cell Survival; D006801:Humans; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000276:immunology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D015398:Signal Transduction / Q000502:physiology*; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000276:immunology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology
chemical_list: D016692:Receptors, Antigen, T-Cell, gamma-delta; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D047390:Casein Kinase II; D051057:Proto-Oncogene Proteins c-akt