Casein Kinase 2 (CK2): A Possible Therapeutic Target in Acute Myeloid Leukemia

Abstract

The protein kinase CK2 (also known as casein kinase 2) is one of the main contributors to the human phosphoproteome. It is regarded as a possible therapeutic strategy in several malignant diseases, including acute myeloid leukemia (AML), which is an aggressive bone marrow malignancy. CK2 is an important regulator of intracellular signaling in AML cells, especially PI3K-Akt, Jak-Stat, NFκB, Wnt, and DNA repair signaling. High CK2 levels in AML cells at the first time of diagnosis are associated with decreased survival (i.e., increased risk of chemoresistant leukemia relapse) for patients receiving intensive and potentially curative antileukemic therapy. However, it is not known whether these high CK2 levels can be used as an independent prognostic biomarker because this has not been investigated in multivariate analyses. Several CK2 inhibitors have been developed, but CX-4945/silmitasertib is best characterized. This drug has antiproliferative and proapoptotic effects in primary human AML cells. The preliminary results from studies of silmitasertib in the treatment of other malignancies suggest that gastrointestinal and bone marrow toxicities are relatively common. However, clinical AML studies are not available. Taken together, the available experimental and clinical evidence suggests that the possible use of CK2 inhibition in the treatment of AML should be further investigated.

Keywords: CK2; acute myeloid leukemia; apoptosis; chemoresistance; chemotherapy; cytokine; prognosis; proliferation; silmitasertib.

Figure 1

Targeting of complex biological networks in AML by CK2 inhibition; TLR4/CK2/NFκB interactions as an example of the complexity of CK2 targeting. NFκB is a common target for downstream TLR4 signaling and CK2-mediated phosphorylation; leukemogenesis/chemosensitivity is thereby modulated through three interacting networks: (i) Cross-talking intracellular signaling pathways (yellow) [9,12,13,14,16,22,71,75,76,77,78], (ii) the local extracellular microenvironment (extracellular matrix and cytokines; green) [76,79,80,81,82,83], and (iii) the cellular network with interactions between the leukemic cells and their neighboring non-leukemic endothelial cells [84,86,87,88,89,90,91], MSC [80,92,93], osteoblasts [76,94,95] and immunocompetent cells [96,97,98,99,100,101] (all in blue). Thus, the effects of TLR4/NFκB intracellular signaling are modulated by CK2-mediated phosphorylation of the common target NFκB.