2. Academic Validation
  3. UHRF1-mediated epigenetic reprogramming regulates glycolysis to promote progression of B-cell acute lymphoblastic leukemia

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

  • Cell Death Dis. 2025 Apr 29;16(1):351. doi: 10.1038/s41419-025-07532-0.
Yan Huang # 1,  Luting Luo # 1 2 3,  Yangqi Xu 1,  Jiazheng Li 4,  Zhengjun Wu 1,  Chenxing Zhao 5,  Jingjing Wen 6,  Peifang Jiang 4,  Haojie Zhu 7,  Lingyan Wang 1,  Yanxin Chen 8,  Ting Yang 9,  Jianda Hu 10 11 12
Affiliations

Affiliations

  • 1 Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China.
  • 2 The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, P.R. China.
  • 3 Institute of Precision Medicine, Fujian Medical University, Fuzhou, Fujian, P.R. China.
  • 4 Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian, P.R. China.
  • 5 Department of Immunology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, P.R. China.
  • 6 Department of Lymphoma, Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, Fuzhou, Fujian, P.R. China.
  • 7 The Second Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, P.R. China.
  • 8 Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China. chenyx158@163.com.
  • 9 The Second Department of Hematology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, P.R. China. yang.hopeting@gmail.com.
  • 10 Fujian Medical University Union Hospital, Fuzhou, Fujian, P.R. China. drjiandahu@163.com.
  • 11 The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, P.R. China. drjiandahu@163.com.
  • 12 Institute of Precision Medicine, Fujian Medical University, Fuzhou, Fujian, P.R. China. drjiandahu@163.com.
  • # Contributed equally.
PMID: 40301374 DOI: 10.1038/s41419-025-07532-0
Abstract

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.

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