UHRF1-mediated epigenetic reprogramming regulates glycolysis to promote progression of B-cell acute lymphoblastic...

The prognosis for adult B-cell acute lymphoblastic leukemia remains unfavorable, especially in the context of relapsed and refractory disease. Exploring the molecular mechanisms underlying disease progression holds significant promise for improving clinical outcomes. In this investigation, utilizing single-cell transcriptome sequencing technology, we discerned a correlation between Ubiquitin-like containing PHD and RING finger domain 1 (UHRF1) and the progression of B-cell acute lymphoblastic leukemia. Our findings reveal a significant upregulation of UHRF1 in cases of relapsed and refractory B-cell acute lymphoblastic leukemia, thereby serving as a prognostic indicator for poor outcomes. Both deletion of UHRF1 or overexpression of its downstream target secreted frizzled-related protein 5 (SFRP5) resulted in the inhibition of leukemia cell proliferation, promoting cellular apoptosis and induction of cell cycle arrest. Our results showed that UHRF1 employs methylation modifications to repress the expression of SFRP5, consequently inducing the WNT5A-P38 MAPK-HK2 signaling axis, resulting in the augmentation of lactate, the critical metabolic product of aerobic glycolysis. Furthermore, we identified UM164 as a targeted inhibitor of UHRF1 that substantially inhibits P38 protein phosphorylation, downregulates HK2 expression, and reduces lactate production. UM164 also demonstrated antileukemic activity both in vitro and in vivo. In summary, our investigation revealed the molecular mechanisms of epigenetic and metabolic reprogramming in relapsed and refractory B-cell acute lymphoblastic leukemia and provides potential targeted therapeutic strategies to improve its inadequate prognosis. The schematic model showed the regulator network of UHRF1-SFRP5-WNT5A-P38 MAPK-HK2 in B-ALL.