Phosphorylated DEK sustains leukemia stem cells by enabling PBX3-driven transcriptional reprogramming

Area of Science:

• Hematology
• Molecular Biology
• Cancer Research

Background:

• Leukemia stem cells (LSCs) drive acute myeloid leukemia (AML) initiation, relapse, and chemoresistance.
• The post-translational modifications sustaining LSC maintenance are not well understood.

Purpose of the Study:

• To identify critical post-translational modifications in LSCs.
• To investigate the role of DEK phosphorylation in AML pathogenesis and therapy.

Main Methods:

• Phosphoproteomic profiling of normal hematopoietic stem and progenitor cells (HSPCs) versus LSCs.
• Functional studies in AML mouse models and patient-derived xenografts (PDXs).
• Investigating the DEK-GABPA-PBX3 interaction and the role of casein kinase 2 (CK2).

Main Results:

• DEK phosphorylation at Ser301/303/306/307 (4S sites) is critical for LSC maintenance and AML progression.
• DEK deficiency impairs LSC maintenance and increases sensitivity to azacitidine/venetoclax (Aza/Ven).
• DEK recruits GABPA to upregulate PBX3, driven by CK2-mediated DEK phosphorylation.
• CK2 inhibitor CX-4945 selectively depletes LSCs and synergizes with venetoclax.

Conclusions:

• DEK-4S phosphorylation is a novel mechanism sustaining LSCs in AML.
• The CK2-DEK axis represents a promising therapeutic target for selective LSC elimination.
• Combining CK2 inhibition with venetoclax shows synergistic anti-AML effects.