CK2 as a therapeutic target in acute lymphoblastic leucemia: the gama-delta subtype

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CK2 as a therapeutic target in acute lymphoblastic leucemia: the gama-delta subtype

Wednesday, 21.12.2016

Authors and Affiliations:

Sérgio T Ribeiro1, Melania Tesio2, Julie C Ribot1, Elizabeth Macintyre2, João T Barata1 and Bruno Silva-Santos1

1Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal

2Institut Necker Enfants Malades, Hôpital Necker-Enfants Malades et Université Paris, France

 

Abstract:

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 TCR-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-ALL cells. When compared to 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.

 

Journal: Leukemia

 

Link: http://www.nature.com/leu/journal/vaop/ncurrent/full/leu2016363a.html