Lineage-specific CK2α deletion reshapes the transcriptome of hematopoietic stem cells toward an immune-primed state

Casein Kinase 2 (CK2) is a constitutively active kinase regulating proliferation and immune signaling and is frequently dysregulated in cancer, including acute myeloid leukemia (AML), making it a therapeutic target. CK2 comprises two catalytic subunits, CK2 or CK2, with two regulatory {beta} subunits. The role of CK2, the predominant catalytic subunit and principal mediator of CK2 kinase activity in hematopoietic cells, in steady-state hematopoiesis remains undefined. To define how CK2 shapes hematopoietic cells, we used bone marrow and spleen tissue samples of wild type control and conditional knock out (KO) of CK2 (Csnk2a1) in the hematopoietic compartment of transgenic mice. Using single-cell RNA sequencing, we profiled the transcriptomic changes associated with CK2 loss. Although HSC abundance was comparable between the control and CK2-deficient samples, HSCs experienced the largest transcriptional response to CK2 loss among all cell types. CK2-deficient HSCs displayed transcriptional remodeling for inflammatory and immune-associated programs, interferon signaling, and antigen presentation. Expression of inflammatory genes such as S100a8 and S100a9, changed in opposite directions in bone marrow and spleen HSCs, demonstrating the transcriptional consequences of CK2 loss shaped by tissue context. Using a network-based approach, we identified immune-associated transcription factors Nfkb1, Rfx5, Hes1, and AP-1 family members as regulatory hubs driving these inflammatory transcriptional states in CK2-deficient HSCs. Cell-cell communication profiling revealed multiple gains and losses in ligand-receptor communication between the HSCs and their immune microenvironment in KO. Our findings identify CK2 as a regulator of immune transcriptional programs in HSCs and suggest that disruption of CK2 signaling influences stem cell behavior and immune activation in contexts relevant to hematologic malignancies and CK2-targeted cancer therapies. Statement of significanceThis study reveals that inhibiting the protein CK2 forces blood stem cells into a stressed, immune-primed state. These tissue-specific findings highlight potential side effects for cancer therapies targeting this essential regulatory kinase.