ENPP2 promotes progression and lipid accumulation via AMPK/SREBP1/FAS pathway in chronic lymphocytic leukemia

Abstract

Abstract Disorders of lipid metabolism are critical factors in the progression of chronic lymphocytic leukemia (CLL). The characteristics of lipid metabolism and related regulatory mechanisms of CLL remain unclear. Hence, we identified altered metabolites in CLL patients by lipidomic to investigate aberrant lipid metabolism pathways. Based on the area under the curve value, a combination of three metabolites (PC O-24:2_18:2, PC O-35:3, and LPC 34:3) potentially served as a biomarker for the diagnosis of CLL. Moreover, utilizing integrated lipidomic, transcriptomic, and molecular studies, we reveal that ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) plays a crucial role in regulating oncogenic lipogenesis. ENPP2 expression was significantly elevated in CLL patients compared to normal cells and was validated in an independent cohort. Besides, ENPP2 knockdown and targeted inhibitor PF-8380 treatment exerted an anti-tumor effect by regulating cell viability, proliferation, apoptosis, cell cycle, and enhanced the drug sensitivity to ibrutinib. Mechanistically, ENPP2 inhibited AMP-activated protein kinase (AMPK) phosphorylation and promoted lipogenesis through the sterol regulatory element-binding transcription factor 1 (SREBP-1)/fatty acid synthase (FAS) signaling pathway to promote lipogenesis. Taken together, our findings unravel the lipid metabolism characteristics of CLL, and highlight the potential role of ENPP2 as a novel therapeutic target for CLL treatment.