Critical role of protein kinase CK2 in chronic myeloid leukemia cells harboring the T315I BCR::ABL1 mutation.

Chronic myeloid leukemia (CML) is characterized by the fusion protein BCR::ABL1, a constitutively active tyrosine kinase. The frontline treatment, represented by tyrosine kinase inhibitors (TKIs), has dramatically improved the clinical outcomes of patients. However, TKI resistance through various mechanisms has been reported. In particular, the BCR::ABL11 T315I mutation is associated with resistance to first- and second-generation TKIs and poor survival outcomes. For patients harboring this mutation, treatments with third generation TKIs are indicated, which are however accompanied by adverse events. Protein kinase CK2 is implicated in several human diseases. Although its role in CML has already been proven, its essentialness in T315I-mediated TKI resistance has yet to be investigated. Here we show that CK2 contributes to the aberrantly high signaling pathways in T315I-cells, and that its pharmacological or genetic targeting diminishes those signals, induces apoptosis, and reduces the proliferation and clonogenic potential of T315I-cells. The effects of CK2 inhibition are also observed in the presence of bone marrow stromal cells and under hypoxic conditions, and, remarkably, in patient-derived cells. Moreover, CK2 inhibition or genetic ablation of the CK2α catalytic subunit sensitizes T315I-cells towards TKIs. Collectively, our results suggest the potential benefit of inhibiting CK2 in CML characterized by T315I-dependent resistance.