{"database":"GEO","file_versions":[],"scores":null,"additional":{"omics_type":["Genomics"],"species":["Homo sapiens"],"gds_type":["Genome binding/occupancy profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE329274"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Phosphorylated DEK sustains leukemia stem cells by enabling PBX3-driven transcriptional reprogramming [CUT&Tag 2]","description":"Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) initiation, relapse, and chemoresistance, yet the core post-translational events governing LSC formation and maintenance remain elusive. Here, through phosphoproteomic profiling of normal hematopoietic stem and progenitor cells (HSPCs) versus LSC-enriched population, we identify DEK phosphorylation as a critical modification during leukemogenesis. Functional studies in MLL-AF9- and HOXA9/MEIS1-driven AML mouse models, as well as patient-derived xenografts (PDXs), demonstrate that DEK deficiency impairs LSC maintenance and AML development. Moreover, DEK deletion enhances LSC chemosensitivity to the standard-of-care combination of azacitidine and venetoclax (Aza/Ven), whereas DEK overexpression confers robust chemoresistance. Mechanistically, DEK recruits the transcription factor GABPA to drive overexpression of transcriptional cofactor PBX3, a key oncogenic driver in AML, thereby sustaining a leukemogenic transcriptional program. This DEK-GABPA interaction strictly depends on DEK phosphorylation at Ser301/303/306/307 (the 4S site), which stabilizes the conformation of the DEK-GABPA complex. We demonstrate CK2 as the upstream kinase that directly phosphorylates DEK-4S site. Importantly, inhibition of DEK phosphorylation through 4S site mutations or treatment with a clinical-stage CK2 inhibitor CX-4945 selectively depletes LSCs while sparing normal HSPCs. Furthermore, combining CX-4945 with venetoclax promotes LSC apoptosis and suppresses the PBX3-mediated leukemogenic transcriptional program, exhibiting synergistic anti-AML effects both in vitro and in vivo. Collectively, our findings uncover a previously unrecognized phosphorylation event (DEK-4S phosphorylation) that sustains LSCs and establish the CK2-DEK axis as a promising LSC-specific therapeutic strategy in AML.","dates":{"publication":"2026/04/28"},"accession":"GSE329274","cross_references":{"GSM":["GSM9700819","GSM9700818","GSM9700820","GSM9700811","GSM9700822","GSM9700821","GSM9700813","GSM9700812","GSM9700815","GSM9700814","GSM9700817","GSM9700816"],"GPL":["24676"],"GSE":["329274"],"taxon":["Homo sapiens"]}}