CK2-mediated DEK Phosphorylation Drives PBX3 Overexpression: A Core Event in Hematopoietic Stem Cell-to-Leukemia Stem Cell Transformation [CUT&Tag]

Leukemia stem cells (LSCs) possess self-renewal capacity and are largely refractory to conventional chemotherapy, thereby driving relapse and treatment failure in acute myeloid leukemia (AML). Here, we identify DEK as a crucial oncogenic factor aberrantly overexpressed in relapsed AML, with markedly increased phosphorylation by casein kinase 2 (CK2), correlating with poor patient prognosis. Using human AML cells and mouse models, we demonstrate that loss of DEK or phospho-mutants DEK, specifically at Ser306/Ser308/Ser311/Ser312 induces AML cells proliferation, differentiation, and weakened LSCs stemness. Mechanistically, phosphorylated DEK recruits GABPA to activate PBX3 transcription, thereby driving a leukemic transcriptional program. Importantly, targeting DEK or pharmacologic inhibition of CK2 using the specific inhibitor CX-4945 disrupts DEK phosphorylation and markedly sensitizes AML cells to venetoclax treatment, providing a rationale for a potential combination therapeutic strategy. Collectively, our findings uncover a unique and critical role of phosphorylated DEK as a transcriptional coactivator in AML and highlight the CK2-DEK/GABPA-PBX3 axis as a promising therapeutic target for AML. L-GMP(Lin-Sca-1-c-Kit+CD16/32+CD34+) from MLL-AF9-driven Wild-type (WT) and Dek-Ser306A/Ser308A/Ser311A/Ser312A(4S-A) AML mice were sorted, followed by DEK-CUT-Tag-seq. L-GMP(Lin-Sca-1-c-Kit+CD16/32+CD34+) from MLL-AF9-driven WT AML mice were sorted, followed by PBX3-CUT-Tag-seq. L-GMP(Lin-Sca-1-c-Kit+CD16/32+CD34+) from MLL-AF9-driven WT, Dekfl/fl,MX1-Cre (KO) and 4S-A AML mice were sorted, followed by GABPA-CUT-Tag-seq.