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 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.

Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells

“…In addition, we showed that the combination of methotrexate and CX-4945 had a synergistic effect on the caspases 3/7 activation in CCRF-CEM cell line. The results are in agreement with the literature data demonstrating that CK2 and its substrates such as serine/threonine kinase AKT protect cells from apoptosis by phosphorylation of a wide range of proteins involved in the apoptotic response (30,31). Consequently, inhibition of CK2 leads to increased apoptosis in many types of cancer cells, including leukemia (32).…”

MicroRNA-146a controls functional plasticity in γδ T cells by targeting NOD1

“…Although we were unable to perform luciferase assays in primary murine 27 − T cells, we successfully validated Nod1 targeting by miR-146a in a human  T cell line ( fig. S7) that we previously showed to be a suitable model to study human  T cell development (28).…”

Treatment response and outcome of children with T-cell acute lymphoblastic leukemia expressing the gamma-delta T-cell receptor

“…Recent studies have shown that the developmental and proliferative programs as well as the expression of genes regulating apoptosis differ between the γδ and αβ lineages. 1,2 Certain neoplasms derived from the γδ T cell lineage such as primary cutaneous and hepatosplenic lymphomas are clinically aggressive with bleak prognoses and are recognized as being biologically distinct. [3][4][5][6][7][8] For patients with T-cell acute lymphoblastic leukemia (T-ALL) expressing the γδ TCR, case reports have suggested that they are at higher risk for poor outcomes.…”